Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof

ABSTRACT

The present invention relates to an oxopicolinamide derivative, a preparation method therefor and the pharmaceutical use thereof. In particular, the present invention relates to an oxopicolinamide derivative as shown in the general formula (AI), a preparation method therefor and a pharmaceutical composition comprising the derivative, and to the use thereof as a therapeutic agent, in particular as an inhibitor of blood coagulation factor XIa (Factor XIa, FXIa for short) and the use thereof in the preparation of a drug for treating diseases such as thromboembolism, wherein the definition of each substituent in the general formula (AI) is the same as defined in the description.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Section 371 of International Application No.PCT/CN2017/099579, filed Aug. 30, 2017, which was published in theChinese language on Mar. 8, 2018, under International Publication No. WO2018/041122 A1, which claims priority under 35 U.S.C. § 119(b) toChinese Application Nos. 201610789384.9, filed Aug. 31, 2016 and201710014133.8, filed Jan. 9, 2017, the disclosures of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a novel class of oxopyridinyl amidederivatives, a preparation method thereof, and a pharmaceuticalcomposition comprising the same, and use thereof as a therapeutic agent,in particular as an inhibitor of blood coagulation factor XIa (FactorXIa, abbreviated as FXIa) and use thereof in the preparation of amedicament for treating and/or preventing diseases such asthromboembolism.

BACKGROUND OF THE INVENTION

Every year, cardiovascular and cerebrovascular diseases such ascerebrovascular, cerebral infarction, myocardial infarction, coronaryheart disease and arteriosclerosis take nearly 12 million lives, whichare close to ¼ of the total death toll in the world, and become thenumber one enemy of human health. The number of people dying fromcardiovascular disease in China each year is more than 2.6 million, and75% of surviving patients are disabled, and more than 40% of them areseverely disabled. The problem of thrombosis caused by cardiovascularand cerebrovascular diseases and diabetes and complications thereof hasbecome an urgent problem to be solved today.

According to Datamonitor 2011 data from independent market analysts,with the production of generic drugs, the share of cardiovascular andmetabolic diseases in the seven major markets will peak in 2011 and thengradually decrease. The sales will decrease from $109 billion in 2010 to$101 billion in 2019. The thrombus market remained basically stable,from $19.5 billion in 2010 to $18.9 billion in 2019 (Datamonitor:HC00034-001, HC00139-001). Guangzhou Punctuation 2011 research reportalso showed that China's anti-thrombotic drug market scale in 2011reached 8.135 billion yuan, year-on-year growth of 20.52%, with hugemarket potential (anti-thrombotic drug market research report: GuangzhouPunctuation (2011)).

The process of human blood coagulation, consisting of an intrinsicpathway, an extrinsic pathway, and a common pathway (Annu. Rev. Med.2011.62:41-57), is a chain reaction in which the process is continuouslyenhanced and amplified by sequential activation of multiple zymogens.The coagulation cascade is initiated by the endogenous pathway (alsoknown as the contact activation pathway) and the exogenous pathway (alsoknown as the tissue factor pathway) to produce FXa, which then formsthrombin (FIIa) by a common pathway, and fibrin is finally formed.

The endogenous pathway refers to the process from the activation offactor XII to the formation of XIa-VIIIa-Ca2+P L complex and theactivation of factor X, and the exogenous coagulation pathway refers tothe process from the release of tissue factor (TF) to the formation ofTF-VIIaCa2+ complex and the activation of factor X. The common pathwayrefers to the process in which after the formation of factor Xa, the twopathways are combined into one, prothrombin is activated, and fibrin isfinally formed, and FXI is necessary for maintaining the endogenouspathway and plays a key role in the amplification of the coagulationcascade. In the coagulation cascade, thrombin feedback activates FXI,and activated FXI (FXIa) in turn promotes the mass production ofthrombin, thereby amplifying the coagulation cascade. Therefore,antagonists of FXI have been extensively developed for the treatment ofvarious thrombi.

Traditional anticoagulant drugs such as warfarin, heparin, low molecularweight heparin (LMWH), and new drugs marketed in recent years, such asFXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors(dabigatran etexilate, hirudin, etc.,) have a good effect on reducingthrombosis, and occupy the majority of cardiovascular andcerebrovascular market with their remarkable effectiveness, but theirside effects are also more and more significant, of which “bleedingrisk” is one of the most serious problems (N. Engl. J. Med. 1991; 325:153-8, Blood. 2003; 101: 4783-4788).

Human FXI deficiency (FXI activity<15 U/dL) is also known as type Chemophilia. This type of patient has a mild bleed phenotype and seldomspontaneous bleeding. Even in the case of injury or surgery, the body'shemostatic function is not affected. Patients with type C hemophilia canbe pregnant normally (Arterioscler Thromb. Vasc. Biol. 2010; 30:388-392). This shows that the safety of FXIa is significantly betterthan that of FXa. Therefore, the target FXIa has become a hot researchtopic among major companies and research institutions. In the thrombusmodel, inhibition of FXIa factor can effectively inhibit thrombusformation, but in the case of more severe thrombosis, FXIa has littleeffect (Blood. 2010; 116 (19): 3981-3989). Clinical statistics show thatincreasing the amount of FXIa increases the prevalence of VTE (Blood2009; 114: 2878-2883), while those with severe FXIa deficiency have areduced risk of suffering from DVT (Thromb. Haemost. 2011; 105:269-273).

FXIa is an emerging target, and patents disclosing compounds having FXIainhibitory activity include WO9630396, WO9941276, WO2013093484,WO2004002405, WO2013056060, WO2017005725, and US20050171148. Among them,only Bayer's antisense oligonucleotides (ASO) BAY-2306001 entered theclinical phase II study and achieved good results. In the clinical PhaseI trial of the drug, the subject's FXI activity showed a sustained,dose-dependent decrease, accompanied by a prolongation of aPTT, even ifthe FXI in the body fell to an undetectable level, there would be nodrug-related hemorrhagic symptoms. The results show the potential ofFXIa as an emerging target (Arterioscler Thromb. Vasc. Biol., 2013,33(7) 1670-1678). However, FXI ASO is administered by injection and hasa slow onset of action. It takes several weeks to form an antithromboticeffect, which may be limited as a preventive drug. In terms of smallmolecule inhibitors, only FXIa inhibitors (BMS company) entered clinicalPhase I in 2014. So far, no clinical results have been reported,therefore, the research of new FXIa inhibitors is of great significance.

The present invention devises a novel small molecule FXIa antagonisthaving the structure of formula (AI), wherein R¹ in the formula isC(O)R⁷, which has a significant improvement on the anticoagulant effectand pharmacological absorption of the entire compound. The compounds ofthe present invention have higher activity than the disclosed patentedcompounds having a similar core structure. In particular, the compoundof the present invention exhibits excellent anticoagulant action againsthuman blood, and has good pharmacokinetic activity, and can be used foreffectively treating and/or preventing cardiovascular andcerebrovascular diseases and thrombotic symptoms.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound of theformula (AI):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or aprodrug thereof,

wherein:

ring A is an aryl or a heteroaryl;

R¹ is —C(O)R⁷;

each R² is identical or different and each is independently selectedfrom the group consisting of hydrogen, halogen, alkyl, haloalkyl,alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl,cycloalkyl, heterocyclyl, aryl and heteroaryl;

R³ is selected from the group consisting of halogen, alkyl, haloalkyl,alkoxy, cycloalkyloxy, haloalkoxy, amino, nitro, cyano, hydroxy,hydroxyalkyl and alkylthio, wherein the alkyl, alkoxy, haloalkyl,haloalkoxy, hydroxyalkyl and alkylthio are each optionally substitutedby one or more groups selected from the group consisting of deuterium,halogen, alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy, andhydroxyalkyl;

R⁴ is selected from the group consisting of hydrogen, alkyl, alkoxy,haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryland heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl are each optionally substituted by one or more R⁹ groups;

each R⁵ is identical or different and each is independently selectedfrom the group consisting of hydrogen, alkyl, alkoxy, oxo, halogen,haloalkyl, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R⁸, —C(O)OR⁸,—NHC(O)R⁸, —NHC(O)OR⁸, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —CH₂NHC(O)OR⁸,—CH₂NR¹⁰R¹¹, —C(O)OCH(R¹⁰)R¹¹ and —S(O)_(m)R⁸, wherein the alkyl isoptionally substituted by one or more groups selected from the groupconsisting of deuterium, halogen, alkoxy, haloalkoxy, amino, nitro,cyano, hydroxy, hydroxyalkyl, —NR¹⁰R¹¹ and —NHC(O)OR⁸;

R⁷ is selected from the group consisting of hydrogen, alkyl, haloalkyl,alkoxy, haloalkoxy, amino, hydroxy, hydroxyalkyl, cycloalkyl,heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionallysubstituted by one or more groups selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, alkoxy, haloalkoxy, amino, nitro,cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl,aryl and heteroaryl;

R⁸ is selected from the group consisting of hydrogen, alkyl, haloalkyl,hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁹ is selected from the group consisting of hydrogen, deuterium,halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy,hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl andheteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroarylare each optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino,nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy,heterocyclyl, —NHC(O)R¹² and R¹³;

R¹⁰ and R¹¹ are identical or different, and each is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,cycloalkyl, heterocyclyl, —C(O)OR⁸ and —OC(O)OR¹², wherein thecycloalkyl and heterocyclyl are each optionally substituted by one ormore groups selected from the group consisting of deuterium, halogen,alkyl, alkoxy, haloalkyl, oxo, amino, nitro, cyano, hydroxy andhydroxyalkyl;

R¹² is selected from the group consisting of hydrogen, alkyl, alkoxy,haloalkyl, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl andheteroaryl;

R¹³ is aryl or heteroaryl, wherein the aryl and heteroaryl are eachoptionally substituted by one or more groups selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl,amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxyand heterocyclyl;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

s is 0, 1, 2, 3 or 4.

In a preferred embodiment of the present invention, the compound offormula (AI) is a compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or aprodrug thereof,

wherein:

L¹ is alkylene, wherein the alkylene is optionally substituted by one ormore halogens or deuteriums;

R⁶ is selected from the group consisting of hydrogen, deuterium,halogen, alkyl, alkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl,cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl, whereinthe cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano,hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl,—NHC(O)R¹² and R¹³;

R¹² is selected from the group consisting of hydrogen, alkyl, haloalkyl,amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹³ is aryl or heteroaryl, wherein the aryl and heteroaryl are eachoptionally substituted by one or more groups selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl,amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxyand heterocyclyl; and

ring A, R¹˜R³, R⁵, n and s are as defined in formula (AI).

In a preferred embodiment of the present invention, the compound offormula (AI) is a compound of formula (Iaa):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or aprodrug thereof,

wherein:

ring A, L¹, R¹˜R³, R⁵˜R⁶, n and s are as defined in formula (I).

In a preferred embodiment of the present invention, in the compound offormula (AI),

is selected from the group consisting of:

wherein R⁵ and s are as defined in formula (AI).

In a preferred embodiment of the present invention, the compound offormula (AI) is a compound of formula (II):

wherein:

R⁷ is selected from the group consisting of alkyl, cycloalkyl andhaloalkyl, wherein the alkyl and cycloalkyl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl and cycloalkyl; and

L¹, R², R³, R⁵, R⁶ and n are as defined in formula (I).

In a preferred embodiment of the present invention, in the compound offormula (AI), each R⁵ is identical or different and each isindependently selected from the group consisting of alkyl, alkoxy, oxo,halogen, haloalkyl, cyano, hydroxy, —C(O)OR⁸, —NHC(O)OR⁸, —C(O)NR¹⁰R¹¹,—CH₂NHC(O)OR⁸, —CH₂NR¹⁰R¹¹, —C(O)OCH(R¹⁰)R¹¹ and —S(O)_(m)R⁸; R⁸ isselected from the group consisting of hydrogen, alkyl, hydroxy andamino; R¹⁰ and R¹¹ are identical or different and each is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,cycloalkyl, heterocyclyl, —C(O)OR⁸ and —OC(O)OR¹², wherein thecycloalkyl and heterocyclyl are each optionally substituted by one ormore groups selected from the group consisting of deuterium, halogen,alkyl, alkoxy, haloalkyl, oxo, amino, nitro, cyano, hydroxy andhydroxyalkyl; and R¹² is alkyl.

In a preferred embodiment of the present invention, in the compound offormula (AI), R¹ is —C(O)R⁷; R⁷ is selected from the group consisting ofalkyl, cycloalkyl and haloalkyl, wherein the alkyl and cycloalkyl areeach optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl and cycloalkyl. In apreferred embodiment of the present invention, the compound of formula(AI) is a compound of formula (III):

wherein:

each R⁵ is identical or different and each is independently selectedfrom the group consisting of alkyl, alkoxy, oxo, halogen, haloalkyl,cyano, hydroxy, —C(O)OR⁸, —NHC(O)OR⁸, —C(O)NR¹⁰R¹¹, —CH₂NHC(O)OR⁸,—CH₂NR¹⁰R¹¹, —C(O)OCH(R¹⁰)R¹¹ and —S(O)_(m)R⁸; R⁸ is selected from thegroup consisting of hydrogen, alkyl, hydroxy and amino; R¹⁰ and R¹¹ areidentical or different and each is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl,—C(O)OR⁸ and —OC(O)OR¹², wherein the cycloalkyl and heterocyclyl areeach optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, oxo,amino, nitro, cyano, hydroxy and hydroxyalkyl; and R¹² is alkyl;

R⁷ is selected from the group consisting of alkyl, cycloalkyl andhaloalkyl, wherein the alkyl and cycloalkyl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl and cycloalkyl; and

L¹, R², R³, R⁶ and n are as defined in formula (I).

In a preferred embodiment of the present invention, the compound offormula (AI) is a compound of formula (IV):

wherein:

L¹, R², R³, R⁶, R⁷ and n are as defined in formula (III).

In a preferred embodiment of the present invention, in the compound offormula (AI), wherein R² is halogen; and n is 0, 1 or 2.

In a preferred embodiment of the present invention, in the compound offormula (AI), R³ is alkoxy, wherein the alkoxy is optionally substitutedby one or more deuteriums or halogens.

In a preferred embodiment of the present invention, in the compound offormula (I), L¹ is —(CR¹⁴ ₂)_(x)—, x is an integer of 1˜4; R¹⁴ ishydrogen or deuterium; R⁶ is selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl,aryl and heteroaryl are each optionally substituted by one or moregroups selected from the group consisting of deuterium, halogen, alkyl,alkoxy, cycloalkyl, heterocyclyl, —NHC(O)R¹² and R¹³; R¹² is alkyl orcycloalkyl; R¹³ is aryl or heteroaryl, wherein the aryl and heteroarylare each optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino,nitro, cyano and hydroxy.

In a preferred embodiment of the present invention, in the compound offormula (AI), L¹ is —CH₂— or —CD₂-, wherein D is deuterium; R⁶ isselected from the group consisting of cycloalkyl, heterocyclyl, aryl andheteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroarylare each optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, cycloalkyl,heterocyclyl, —NHC(O)R¹² and R¹³; R¹² is alkyl or cycloalkyl; R¹³ isaryl or heteroaryl, wherein the aryl and heteroaryl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano andhydroxy.

In a preferred embodiment of the present invention, in the compound offormula (AI), L¹ is —CH₂CH₂—; and R⁶ is alkyl, alkoxy or cycloalkyloxy.

Typical compounds of formula (AI), include, but are not limited to:

Example No. Structure and Name  1 1

5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylic acid  1i 1i

ethyl5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybulanamido)-1H-indole-2-carboxylate 1i  2 2

(S)-5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylic acid 2  3 3

(R)-5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylic acid 3  4d 4d

methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 4d  4 4

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 4  5 5

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 5  6 6

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 6  7f 7f

methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiophen-3-yl)propanamido)benzoate 7f  7 7

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiophen-3-yl)propanamido)benzoic acid 7  8 8

4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 8  9 9

(S)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 9  10 10

(R)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenvlpropanamido)benzoic acid 10  11 11

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide 11  12 12

methyl (S)-(4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)phenyl)carbamate 12  13 13

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N-methylbenzamide 13  14e 14e

((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 14e  14 14

(R)-((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 14  15 15

(S)-((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 15  16g 16g

methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-(cyclopropanecarboxamido)phenyl)propanamido)benzoate 16g  16 16

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-(cyclopropanecarboxamido)phenyl)propanamido)benzoic acid 16  17f17f

methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4′-cyano-2′-methyl-[1,1′-biphenyl]-4-yl)propanamido)benzoate 17f  1717

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4′-cyano-2′-methyl-[1,1′-biphenyl]-4-yl)propanamido)benzoic acid 17 18 18

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 18  19 19

(R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 19  20 20

(S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 20  21 21

4-(2-(4-(2-butyryl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 21  22 22

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-2-fluorobenzamide 22  23 23

2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(quinazolin-6-yl)propanamide 23  24 24

4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide 24  25 25

(R)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide 25  26 26

(S)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide 26  27 27

2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-indazol-6-yl)-3-phenylpropanamide 27  28 28

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-cyano-1H-indole-6-yl)-3-phenylpropanamide 28  29 29

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-3-fluorobenzoic acid 29  30e 30e

4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 30e  30 30

4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 30  31 31

(S)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 31  32 32

(R)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 32  33 33

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-imidazo[4,5-b]pyridin-5-yl)-3-phenylpropanamide 33  34 34

methyl(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 34  35 35

4-(2-(4-(5-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 35  36 36

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-cyano-3-methoxyphenyl)-3-phenylpropanamide 36  37 37

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N-ethylbenzamide 37  38 38

N-(1H-benzo[d]imidazol-5-yl)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 38  39 39

4-(2-(4-(5-chloro-2-(2-cyclopropylacetyl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid  40 40

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(quinazolin-6-yl)propanamide 40  41 41

4-(2-(4-(5-chloro-2-(cyclopropanecarbonyl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 41  42 42

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-indazol-6-yl)-3-phenylpropanamide 42  43 43

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N-cyclopropylbenzamide 43  44 44

4-(2-(4-(5-chloro-2-isobutyrylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 44  45 45

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide 45  46 46

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(isoquinolin-6-yl)-3-phenylpropanamide 46  47 47

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-benzo[d]imidazol-5-yl)-3-phenylpropanamide 47  48 48

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanamide 48 49 49

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-1H-benzo[d]imidazol-5-yl)-3-phenylpropanamide 49  50 50

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N,N-dimethylbenzamide 50  51 51

5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-2-picolinamide 51  52 52

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(1H-pyrrolo[3,2-b]pyridin-6-yl)propanamide 52  53b 53b

tert-butyl3-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzylcarbamate 53b  53c 53c

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(aminomethyl)phenyl)-3-phenylpropanamide 53c  53 53

methyl3-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzylcarbamate 53  54 54

2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-cyano-1H-indol-6-yl)-3-phenylpropanamide 54  55 55

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-cyano-3-(tnfluoromethyl)phenyl)-3-phenylpropanamide 55  56 56

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(methylsulfonyl)phenyl)-3-phenylpropanamide 56  57 57

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1,6-naphthyridin-3-yl)-3-phenylpropanamide 57  58 58

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(4-sulfamoylphenyl)propanamide 58  59 59

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-cyano-2-fluorophenyl)-3-phenylpropanamide 59  60 60

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3- phenylpropanamide 60 61 61

(S)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 61  62 62

(R)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 62  63 63

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)benzoic acid 63  64 64

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-bromophenyl)propanamido)benzoic acid 64  65 65

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2,4-difluorophenyl)propanamido)benzoic acid 65  66 66

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(o-tolyl)propanamido)benzoic acid 66  67 67

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(m-tolyl)propanamido)benzoic acid 67  68 68

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-fluorophenyl)propanamido)benzoic acid 68  69 69

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-chlorophenyl)propanamido)benzoic acid 69  70 70

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-chlorophenyl)propanamido)benzoic acid 70  71 71

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-methoxyphenyl)propanamido)benzoic acid 71  72 72

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-methoxyphenyl)propanamido)benzoic acid 72  73 73

methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-chlorophenyl)propanamido)benzoate 73  74 74

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(p-tolyl)propanamido)benzoic acid 74  75 75

4-(3-(4-acetamidophenyl)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propanamido)benzoic acid 75  76 76

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2,6-dichlorophenyl)propanamido)benzoic acid 76  77 77

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(5-fluoro-2-methylphenyl)propanamido)benzoic acid 77  78 78

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-methoxyphenyl)propanamido)benzoic acid 78  79 79

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzoic acid 79  80 80

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzoic acid 80  81 81

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzoic acid 81  82 82

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-3-yl)propanamido)benzoic acid 82  83 83

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-3-yl)propanamido)benzoic acid 83  84 84

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-3-yl)propanamido)benzoic acid 84  85 85

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzamide 85  86 86

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-4-yl)propanamido)benzoic acid 86  87 87

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-cyanophenyl)propanamido)benzoic acid 87  88 88

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-cyanophenyl)propanamido)benzoic acid 88  89 89

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-cyanophenyl)propanamido)benzoic acid 89  90 90

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-cyanophenyl)propanamido)benzoic acid 90  91 91

4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoic acid 91  92 92

(S)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoic acid 92 93 93

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoic acid 93  94 94

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoic acid 94  95 95

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoic acid 95  96 96

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)-N-(quinoxalin-6-yl)propanamide 96  97 97

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl) propanamide97  98 98

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)-N-(quinazolin-6-yl)propanamide 98  99 99

4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoic acid 99 100 100

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoic acid 100 101 101

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoic acid 101 102 102

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoic acid 102 103 103

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)benzoic acid 103 104 104

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)benzoic acid 104 105 105

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)benzoic acid 105 106 106

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(isoxazol-5-yl)propanamido)benzoic acid 106 107 107

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiazol-2-yl)propanamido)benzoic acid 107 108e 108e

4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoic acid 108e 108 108

(S)-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoic acid 108 109 109

(R)-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoic acid 109 110 110

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoic acid 110 111 111

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoic acid 111 112 112

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoic acid 112 113 113

4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinoxalin-6-yl)butanamide 113 114 114

(S)-4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinoxalin-6-yl)butanamide 114 115 115

(R)-4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinoxalin-6-yl)butanamide 115 116 116

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(1-oxoisoindolin-5-yl)butanamide 116 117d 117d

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide 117d 117 117

(R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide 117 118 118

(S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)bulanamide 118 119 119

5-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-1H-indole-2-carboxylic acid 119 120 120

4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoic acid 120 121 121

4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinazolin-6-yl)butanamide 121 122 122

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzamide 122 123 123

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)-N-methylbenzamide 123 124 124

4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2,3-dimethylquinoxalin-6-yl)butanamide 124 125125

4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-cyano-1H-indol-6-yl)butanamide 125 126 126

N-(benzo[d]thiazol-5-yl)-4-(tert-butoxy)-2-(4-(5-chloro-2-propionyl-phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamide 126 127 127

4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)thiophene-2-carboxylic acid 127 128 128

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3,4-dihydro-2H-benzo[d][1,4]oxazin-6-yl)butanamide 128129 129

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3-fluorophenyl)butanamide 129 130 130

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(5-chloropyridin-3-yl)butanamide 130 131 131

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(5-fluoropyridin-3-yl)butanamide 131 132 132

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(4-fluorophenyl)butanamide 132 133 133

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3,4-dihydro-2H-benzo[d][1,4]oxazin-7-yl)butanamide 133134 134

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(6-methoxypyridin-3-yl)butanamide 134 135 135

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3-(trifluoromethyl)phenyl)butanamide 135 136 136

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(4-(trifluoromethyl)phenyl)butanamide 136 137 137

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)butanamide 137 138138

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3,4-dihydro-2H-benzo[d][1,4]oxazin-5-yl)butanamide 138139 139

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanamide 139 140140

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(benzo[d][1,3]dioxol-5-yl)-4-(tert-butoxy)butanamide 140 141 141

4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-carbazol-5-yl)butanamide 141 142 142

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(1H-indol-4-yl)butanamide 142 143 143

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)butanamide 143144 144

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2-oxoindolin-6-yl)butanamide 144 145 145

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2-oxoindolin-5-yl)butanamide 145 146 146

4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)benzoic acid 146 147 147

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)benzoic acid 147 148 148

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-2-fluorobenzoic acid 148 149 149

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-2-methoxybenzoic acid 149 150 150

2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-methoxybutanamide 150 151151

1-((ethoxycarbonyl)oxy)ethyl5-((R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate 151 152 152

1-((ethoxycarbonyl)oxy)ethyl5-((S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate 152 153 153

(5-methyl-2-oxo-1,3-dioxal-4-yl)methyl(R)-5-(2-(4-(2-acetyl-5-chlorophenyl))-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate 153 154 154

(5-methyl-2-oxo-1.3-dioxol-4-yl)methyl(S)-5-(2-(4-(2-acetyl-5-chlorophenyl))-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate 154 155 155

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)hexanamido)benzoic acid 155 156 156

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propanamido)benzoic acid 156 157 157

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoic acid 157 158 158

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methylcyclopropyl)propanamido)benzoic acid 158 159 159

4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoic acid 159 160 160

(R)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoic acid 160 161 161

(S)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoic acid 161 162 162

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-cyclobutoxybutanamido)benzoic acid 162 163 163

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-cyclobutoxybutanamido)benzoic acid 163 164 164

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-cyclobutoxybutanamido)benzoic acid 164 165h 165h

methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1R,4R)-4-hydroxycyclohexyl)propanamido)benzoate 165h 165 165

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1r,4r)-4-hydroxycyclohexyl)propanamido)benzoic acid 165 166 166

4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran)-2-yl)propanamido)benzoic acid 166 167 167

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanamido)benzoic acid 167 168 168

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanamido)benzoic acid 168 169 169

4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanamido)benzoic acid 169 170 170

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoic acid 170 171 171

(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoic acid 171 172 172

(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoic acid 172 173 173

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3,3-dimethylcyclobutyl)propanamido)benzoic acid 173 174 174

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydrofuran-2-yl)propanamido)benzoic acid 174 175 175

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-methoxycyclohexyl)propanamido)benzoic acid 175 176 176

4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-2-yl)propanamido)benzoic acid 176 177h 177h

4-[[4-tert-butoxy-2-[4-(5-chloro-2-propionylphenyl)-2-oxo-5-(tri-deuteromethoxy)-1-pyridyl]butyryl]amino]benzoic acid 177h 177 177

4-[[(2S)-4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(tri-deuteromethoxy)-1-pyridyl]butyryl]amino]benzoic acid 177 178 178

4-[[(2R)-4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyryl]amino]benzoic acid 178 179e 179e

4-[[2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoic acid 179e 179 179

4-[[(2S)-2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoic acid 179 180 180

4-[[(2R)-2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoic acid 180 181f 181f

4-[[2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino]benzoic acid181f 181 181

4-[[(2S)-2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]ainino] benzoicacid 181 182 182

4-[[(2R)-2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino] benzoicacid 182 183g 183g

4-[[2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoic acid 183g 183 183

4-[[(2S)-2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoic acid 183 184 184

4-[[(2R)-2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoic acid 184

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or aprodrug thereof.

In a preferred embodiment of the present invention, the presentinvention is directed to a process for preparing the compound of formula(AI), comprising a step of:

condensing a compound of formula (AI-A) with a compound of formula(AI-B) or a hydrochloride thereof under an alkaline condition,optionally hydrolyzing the condensation product under an alkalinecondition to obtain a compound of formula (AI);

wherein:

ring A, R¹˜R⁵, n and s are as defined in formula (AI).

In a preferred embodiment of the present invention, the presentinvention is directed to a process for preparing the compound of formula(I), comprising a step of:

condensing a compound of formula (I-A) with a compound of formula (AI-B)or a hydrochloride thereof under an alkaline condition, optionallyhydrolyzing the condensation product under an alkaline condition toobtain a compound of formula (I);

wherein:

ring A, L¹, R¹˜R³, R⁵˜R⁶, n and s are as defined in formula (I).

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of formula (AI), or a tautomer, mesomer, racemate, enantiomer,diastereomer thereof, or mixture thereof, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, diluents or excipients.

In another aspect, the present invention is directed to the compound offormula (AI), or a tautomer, mesomer, racemate, enantiomer, diastereomerthereof, or mixture thereof, or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition comprising the same for useas a medicament.

In another aspect, the present invention is directed to use of thecompound of formula (AI), or a tautomer, mesomer, racemate, enantiomer,diastereomer thereof, or mixture thereof, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition comprisingthe same in the preparation of a medicament for inhibiting factor XIa.

In another aspect, the present invention is directed to the compound offormula (AI), or a tautomer, mesomer, racemate, enantiomer, diastereomerthereof, or mixture thereof, or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition comprising the same for useas a factor XIa inhibitor.

In another aspect, the present invention is directed to use of thecompound of formula (AI), or a tautomer, mesomer, racemate, enantiomer,diastereomer thereof, or mixture thereof, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition comprisingthe same in the preparation of a medicament for preventing and/ortreating a factor XIa mediated disease.

In another aspect, the present invention is directed to use of thecompound of formula (AI), or a tautomer, mesomer, racemate, enantiomer,diastereomer thereof, or mixture thereof, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition comprisingthe same in the preparation of a medicament for preventing and/ortreating a cardiovascular and cerebrovascular disease, wherein thecardiovascular disease is preferably thromboembolic disease, and morepreferably myocardial infarction, angina pectoris, angioplasty orreocclusion and restenosis after aortic coronary artery shunt,disseminated intravascular coagulation, stroke, transient ischemicattack, peripheral arterial occlusive disease, pulmonary embolism ordeep vein thrombosis.

In another aspect, the present invention is directed to a method forpreventing and/or treating a factor XIa mediated disease, comprising astep of administering to a patient in need thereof a therapeuticallyeffective amount of the compound of formula (AI), or a tautomer,mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof,or a pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition comprising the same.

In another aspect, the present invention is also directed to a methodfor preventing and/or treating a cardiovascular and cerebrovasculardisease, comprising a step of administering to a patient in need thereofa therapeutically effective amount of the compound of formula (AI), or atautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition comprising the same, wherein thecardiovascular and cerebrovascular disease is selected from the groupconsisting of myocardial infarction, angina pectoris, angioplasty orreocclusion and restenosis after aortic coronary artery shunt, stroke,transient ischemic attack, peripheral arterial occlusive disease,pulmonary embolism or deep vein thrombosis.

In another aspect, the present invention is directed to a medicament forinhibiting factor XIa, comprising the compound of formula (AI), or atautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition comprising the same.

Pharmaceutical compositions containing the active ingredient can be in aform suitable for oral administration, for example, a tablet, troche,lozenge, aqueous or oily suspension, dispersible powder or granule,emulsion, hard or soft capsule, or syrup or elixir. Oral compositionscan be prepared according to any method known in the art for thepreparation of pharmaceutical compositions. Such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservatives,in order to provide a pleasing and palatable pharmaceutical formulation.The tablet contains the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients suitable for the manufacture of atablet. These excipients can be inert excipients, granulating agents,disintegrating agents, binders or lubricants. The tablet can be uncoatedor coated by means of a known technique to mask drug taste or delay thedisintegration and absorption of the active ingredient in thegastrointestinal tract, thereby providing sustained release over anextended period.

Oral formulations can be provided as soft gelatin capsules in which theactive ingredient is mixed with an inert solid diluent, or the activeingredient is mixed with a water-soluble carrier or an oil medium orolive oil.

An aqueous suspension contains the active ingredient in admixture withexcipients suitable for the manufacture of an aqueous suspension. Suchexcipients are suspending agents, dispersants or humectants. The aqueoussuspension can also contain one or more preservatives, one or morecoloring agents, one or more flavoring agents, or one or more sweeteningagents.

An oil suspension can be formulated by suspending the active ingredientin a vegetable oil. The oil suspension can contain a thickener. Theaforementioned sweetening agents and flavoring agents can be added toprovide a palatable preparation. These compositions can be preserved byadding an antioxidant.

The active ingredient in admixture with the dispersing or wettingagents, suspending agents or one or more preservatives can be preparedas a dispersible powder or granule suitable for the preparation of anaqueous suspension by adding water. Suitable dispersant or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, such as sweetening, flavoring, andcoloring agents, can also be added. These compositions can be preservedby adding an antioxidant such as ascorbic acid.

The present pharmaceutical composition of the present invention can alsobe in the form of an oil-in-water emulsion. The oil phase can be avegetable oil, or a mineral oil, or a mixture thereof. Suitableemulsifying agents can be naturally occurring phospholipids. Theemulsions can also contain sweetening agents, flavoring agents,preservatives and antioxidants. Such preparations may also containdemulcents, preservatives, coloring agents and antioxidants.

The pharmaceutical composition of the present invention can be in theform of a sterile aqueous solution. Acceptable vehicles or solvents thatcan be used are water, Ringer's solution or isotonic sodium chloridesolution. The sterile injectable preparation can also be a sterileinjectable oil-in-water microemulsion in which the active ingredient isdissolved in the oil phase. The injectable solution or microemulsion canbe introduced into an individual's bloodstream by local bolus injection.Alternatively, the solution and microemulsion are preferablyadministered in a manner that maintains a constant circulatingconcentration of the compound of the present invention. In order tomaintain this constant concentration, a continuous intravenous deliverydevice can be used. An example of such a device is Deltec CADD-PLUS.5400 intravenous injection pump.

The pharmaceutical composition of the present invention can be in theform of a sterile injectable aqueous or oily suspension forintramuscular and subcutaneous administration. Such suspension can beformulated with suitable dispersants or wetting agents and suspendingagents as described above according to known techniques. The sterileinjectable preparation can also be a sterile injectable solution orsuspension prepared in a nontoxic parenterally acceptable diluent orsolvent. Moreover, sterile fixed oils can easily be used as a solvent orsuspending medium. For this purpose, any blended fixed oil can be used.In addition, fatty acids can also be used to prepare injections.

The present compound can be administrated in the form of a suppositoryfor rectal administration. These pharmaceutical compositions can beprepared by mixing a drug with a suitable non-irritating excipient whichis solid at ordinary temperatures but liquid in rectum, thereby meltingin the rectum to release the drug.

It is well known to those skilled in the art that the dosage of a drugdepends on a variety of factors including, but not limited to, thefollowing factors: activity of a specific compound, age of the patient,weight of the patient, general health of the patient, behavior of thepatient, diet of the patient, administration time, administration route,excretion rate, drug combination and the like. In addition, the besttreatment, such as treatment mode, daily dose of the compound of formula(I) or the type of pharmaceutically acceptable salt thereof can beverified by traditional therapeutic regimens.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the terms used in the specification and claimshave the meanings described below.

The term “alkyl” refers to a saturated aliphatic hydrocarbon groupincluding C₁ to C₂₀ linear chain and branched chain groups, preferablyan alkyl having 1 to 12 carbon atoms, and more preferably an alkylhaving 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl,n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl,3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl,2,2-diethylhexyl, and branched isomers thereof. More preferably, analkyl group is a lower alkyl having 1 to 6 carbon atoms, andnon-limiting examples include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl,3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can besubstituted or unsubstituted. When substituted, the substituent group(s)can be substituted at any available connection point. The substituentgroup(s) is preferably one or more groups independently selected fromthe group consisting of deuterium, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy,heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, —C(O)R⁸,—C(O)OR⁸ and —S(O)_(m)R⁸.

The term “alkylene” refers to a saturated linear or branched aliphatichydrocarbon group having two residues derived from the removal of twohydrogen atoms from the same carbon atom or two different carbon atomsof the parent alkane. The linear or branched alkylene has 1 to 20 carbonatoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6carbon atoms. Non-limiting examples of alkylene groups include, but arenot limited to, methylene (—CH₂—), 1,1-ethylene (—CH(CH₃)—),1,2-ethylene (—CH₂CH₂)—, 1,1-propylene (—CH(CH₂CH₃)—), 1,2-propylene(—CH₂CH(CH₃)—), 1,3-propylene (—CH₂CH₂CH₂—), 1,4-butylene(—CH₂CH₂CH₂CH₂—), and the like. The alkylene group can be substituted orunsubstituted. When substituted, the substituent group(s) can besubstituted at any available connection point. The substituent group(s)is preferably one or more groups independently selected from the groupconsisting of deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy,cycloalkylthio, heterocyclylthio, oxo, —C(O)R⁸, —C(O)OR⁸ and—S(O)_(m)R⁸.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms,preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms,and most preferably 3 to 5 carbon atoms. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptatrienyl, cyclooctyl, and the like, and preferably cycloalkyl.Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fusedring or bridged ring.

The term “spiro cycloalkyl” refers to a 5 to 20 membered polycyclicgroup with rings connected through one common carbon atom (called aspiro atom), wherein one or more rings can contain one or more doublebonds, but none of the rings has a completely conjugated pi-electronsystem, preferably 6 to 14 membered spiro cycloalkyl, and morepreferably 7 to 10 membered spiro cycloalkyl. According to the number ofthe spiro atoms shared between the rings, spiro cycloalkyl can bedivided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spirocycloalkyl, and preferably a mono-spiro cycloalkyl or di-spirocycloalkyl, and more preferably 4-membered/4-membered,4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or5-membered/6-membered mono-spiro cycloalkyl. Non-limiting examples ofspiro cycloalkyls include:

The term “fused cycloalkyl” refers to a 5 to 20 membered all-carbonpolycyclic group, wherein each ring in the system shares an adjacentpair of carbon atoms with another ring, wherein one or more rings cancontain one or more double bonds, but none of the rings has a completelyconjugated pi-electron system, preferably 6 to 14 membered fusedcycloalkyl, and more preferably 7 to 10 membered fused cycloalkyl.According to the number of membered rings, fused cycloalkyl can bedivided into bicyclic, tricyclic, tetracyclic or polycyclic fusedcycloalkyl, preferably bicyclic, or tricyclic fused cycloalkyl, and morepreferably 5-membered/5-membered, or 5-membered/6-membered bicyclicfused cycloalkyl. Non-limiting examples of fused cycloalkyls include:

The term “bridged cycloalkyl” refers to a 5 to 20 membered all-carbonpolycyclic group, wherein every two rings in the system share twodisconnected carbon atoms, wherein the rings can have one or more doublebonds, but none of the rings has a completely conjugated pi-electronsystem, preferably 6 to 14 membered bridged cycloalkyl, and morepreferably 7 to 10 membered bridged cycloalkyl. According to the numberof membered rings, bridged cycloalkyl can be divided into bicyclic,tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferablybicyclic, tricyclic or tetracyclic bridged cycloalkyl, and morepreferably bicyclic or tricyclic bridged cycloalkyl. Non-limitingexamples of bridged cycloalkyls include:

The ring of cycloalkyl can be fused to the ring of aryl, heteroaryl orheterocyclyl, wherein the ring bound to the parent structure iscycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl,benzocycloheptyl and the like, preferably benzocyclopentyl,tetrahydronaphthyl. The cycloalkyl can be optionally substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol,hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo,—C(O)R⁸, —C(O)OR⁸ and —S(O)_(m)R⁸.

The term “heterocyclyl” refers to a 3 to 20 membered saturated orpartially unsaturated monocyclic or polycyclic hydrocarbon group havingone or more heteroatoms selected from the group consisting of N, O, andS(O)_(m) (wherein m is an integer of 0 to 2) as ring atoms, butexcluding —O—O—, —O—S— or —S—S— in the ring, with the remaining ringatoms being carbon atoms. Preferably, heterocyclyl has 3 to 12 atoms,wherein 1 to 4 atoms are heteroatoms, more preferably 3 to 8 atoms,wherein 1 to 3 atoms are heteroatoms, and most preferably 3 to 5 atoms,wherein 1 to 2 or 1 to 3 atoms are heteroatoms. Non-limiting examples ofmonocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,dihydroimidazolyl, dihydrofuranyl, dioxole, dihydropyrazolyl,dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,homopiperazinyl and the like. Polycyclic heterocyclyl includes aheterocyclyl having a spiro ring, fused ring or bridged ring.

The term “spiro heterocyclyl” refers to a 5 to 20 membered polycyclicheterocyclyl with rings connected through one common atom (called aspiro atom), wherein the rings have one or more heteroatoms selectedfrom the group consisting of N, O, and S(O)_(m) (wherein m is an integerof 0 to 2) as ring atoms, with the remaining ring atoms being carbonatoms, wherein one or more rings can contain one or more double bonds,but none of the rings has a completely conjugated pi-electron system,preferably 6 to 14 membered spiro heterocyclyl, and more preferably 7 to10 membered spiro heterocyclyl. According to the number of the spiroatoms shared between the rings, spiro heterocyclyl can be divided intomono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiroheterocyclyl, preferably mono-spiro heterocyclyl or di-spiroheterocyclyl, and more preferably 4-membered/4-membered,4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or5-membered/6-membered mono-spiro heterocyclyl. Non-limiting examples ofspiro heterocyclyls include:

The term “fused heterocyclyl” refers to a 5 to 20 membered polycyclicheterocyclyl group, wherein each ring in the system shares an adjacentpair of atoms with another ring, wherein one or more rings can containone or more double bonds, but none of the rings has a completelyconjugated pi-electron system, and wherein the rings have one or moreheteroatoms selected from the group consisting of N, O, and S(O)_(m)(wherein m is an integer of 0 to 2) as ring atoms, with the remainingring atoms being carbon atoms; preferably 6 to 14 membered fusedheterocyclyl, and more preferably 7 to 10 membered fused heterocyclyl.According to the number of membered rings, fused heterocyclyl can bedivided into bicyclic, tricyclic, tetracyclic or polycyclic fusedheterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, andmore preferably 5-membered/5-membered, or 5-membered/6-membered bicyclicfused heterocyclyl. Non-limiting examples of fused heterocyclylsinclude:

The term “bridged heterocyclyl” refers to a 5 to 14 membered polycyclicheterocyclyl group, wherein every two rings in the system share twodisconnected atoms, wherein the rings can have one or more double bonds,but none of the rings has a completely conjugated pi-electron system,and the rings have one or more heteroatoms selected from the groupconsisting of N, O, and S (O)_(m) (wherein m is an integer of 0 to 2) asring atoms, with the remaining ring atoms being carbon atoms, preferably6 to 14 membered bridged heterocyclyl, and more preferably 7 to 10membered bridged heterocyclyl. According to the number of memberedrings, bridged heterocyclyl can be divided into bicyclic, tricyclic,tetracyclic or polycyclic bridged heterocyclyl, and preferably bicyclic,tricyclic or tetracyclic bridged heterocyclyl, and more preferablybicyclic or tricyclic bridged heterocyclyl. Non-limiting examples ofbridged heterocyclyls include:

The heterocyclyl ring can be fused to the ring of an aryl, heteroaryl orcycloalkyl, wherein the ring bound to the parent structure isheterocyclyl. Non-limiting examples include:

etc.

The heterocyclyl can be optionally substituted or unsubstituted. Whensubstituted, the substituent group(s) is preferably one or more groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy,heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, —C(O)R⁸,—C(O)OR⁸ and —S(O)_(m)R⁸.

The term “aryl” refers to a 6 to 20 membered all-carbon monocyclic ringor polycyclic fused ring (i.e. each ring in the system shares anadjacent pair of carbon atoms with another ring in the system) having acompletely conjugated pi-electron system, preferably 6 to 10 memberedaryl, and more preferably 6 membered aryl, for example, phenyl andnaphthyl. The aryl ring can be fused to the ring of heteroaryl,heterocyclyl or cycloalkyl, wherein the ring bound to the parentstructure is the aryl ring. Non-limiting examples include:

The aryl can be optionally substituted or unsubstituted. Whensubstituted, the substituent group(s) is preferably one or more groupsindependently selected from the group consisting of deuterium, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol,hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio,—C(O)R⁸, —C(O)OR⁸ and —S(O)_(m)R⁸.

“Heteroaryl” refers to a 5 to 20 membered heteroaromatic system having 1to 4 heteroatoms selected from the group consisting of O, S and N asring atoms, preferably 5 to 10 membered heteroaryl having 1 to 3heteroatoms, and more preferably 5 or 6 membered heteroaryl having 1 to2 heteroatoms, for example, imidazolyl, furyl, thienyl, thiazolyl,pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl,pyrimidinyl, thiadiazolyl, pyrazinyl and the like. The heteroaryl ringcan be fused to the ring of an aryl, heterocyclyl or cycloalkyl, whereinthe ring bound to the parent structure is heteroaryl ring. Non-limitingexamples include:

The heteroaryl can be optionally substituted or unsubstituted. Whensubstituted, the substituent group(s) is preferably one or more groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy,heterocyclyloxy, cycloalkylthio, heterocyclylthio, —C(O)R⁸, —C(O)OR⁸ and—S(O)_(m)R⁸.

The term “alkoxy” refers to an —O-(alkyl) or an —O-(unsubstitutedcycloalkyl) group, wherein the alkyl is as defined above. Non-limitingexamples include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxycan be optionally substituted or unsubstituted. When substituted, thesubstituent is preferably one or more groups independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy,cycloalkylthio, heterocyclylthio, —C(O)R⁸, —C(O)OR⁸ and —S(O)_(m)R⁸.

The term “alkylthio” refers to a —S-(alkyl) and —S-(unsubstitutedcycloalkyl) group, wherein the alkyl is as defined above. Non-limitingexamples of alkylthio include: methylthio, ethylthio, propylthio,butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio,cyclohexylthio. The alkylthio can be optionally substituted orunsubstituted. When substituted, the substituent is preferably one ormore groups independently selected from the group consisting of alkyl,alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol,hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio,—C(O)R⁸, —C(O)OR⁸ and —S(O)_(m)R⁸.

The term “cycloalkyloxy” refers to a —O-cycloalkyl group, wherein thecycloalkyl is as defined above.

The term “haloalkyl” refers to an alkyl substituted by halogen(s),wherein the alkyl is as defined above.

The term “haloalkoxy” refers to an alkoxy substituted by halogen(s),wherein the alkoxy is as defined above.

The term “hydroxyalkyl” refers to an alkyl substituted by hydroxy(s),wherein the alkyl is as defined above.

The term “hydroxy” refers to an —OH group.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term “amino” refers to an —NH₂ group.

The term “cyano” refers to a —CN group.

The term “nitro” refers to an —NO₂ group.

The term “carboxy” refers to a —C(O)OH group.

The term “alkoxycarbonyl” refers to a —C(O)O(alkyl) or—C(O)O(cycloalkyl) group, wherein the alkyl and cycloalkyl are asdefined above.

“Optional” or “optionally” means that the event or circumstancedescribed subsequently can, but need not occur, and this descriptionincludes the situation in which the event or circumstance does or doesnot occur. For example, “the heterocyclic group optionally substitutedby an alkyl” means that an alkyl group can be, but need not be, present,and this description includes the situation of the heterocyclic groupbeing substituted by an alkyl and the heterocyclic group being notsubstituted by an alkyl.

“Substituted” refers to one or more hydrogen atoms in a group,preferably up to 5, more preferably 1 to 3 hydrogen atoms, independentlysubstituted by a corresponding number of substituents. It goes withoutsaying that the substituents only exist in their possible chemicalpositions. The person skilled in the art is able to determine whetherthe substitution is possible or impossible by experiments or theorywithout paying excessive efforts. For example, the combination of aminoor hydroxy having free hydrogen and carbon atoms having unsaturatedbonds (such as olefinic) can be unstable.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds according to the present invention orphysiologically/pharmaceutically acceptable salts or prodrugs thereofwith other chemical ingredients, and other components such asphysiologically/pharmaceutically acceptable carriers and excipients. Thepurpose of a pharmaceutical composition is to facilitate administrationof a compound to an organism, which is conducive to the absorption ofthe active ingredient, thus displaying biological activity.

A “pharmaceutically acceptable salt” refers to a salt of the compound ofthe present invention, which is safe and effective in mammals and hasthe desired biological activity.

R⁸ and m are as defined in formula (AI).

Synthesis Method of the Compound of the Present Invention

In order to achieve the object of the present invention, the presentinvention applies the following technical solutions.

A process for preparing a compound of formula (AI) of the presentinvention, or a tautomer, mesomer, racemate, enantiomer, diastereomer,or mixture thereof, or a pharmaceutically acceptable salt thereof,comprises the following steps:

wherein:

X is halogen, preferably bromine;

R^(a) is alkyl, preferably methyl;

ring A, R¹˜R⁵, n and s are as defined in the formula (AI).

in the first step reaction, a compound of formula (AI-1) and a compoundof formula (AI-2) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (AI-3); or a compound of formula (AI-1) and a compound offormula (AI-2′) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (AI-A);

in the second step reaction, the compound of formula (AI-3) ishydrolyzed under an acidic condition to obtain a compound of (AI-A);

in the third step, the compound of formula (AI-A) and a compound offormula (AI-B) or a hydrochloride thereof are subjected to acondensation reaction under an alkaline condition, optionally thecondensation product is hydrolyzed under an alkaline condition, toobtain the compound of formula (AI).

The reagents that provide an alkaline condition include organic basesand inorganic bases. The organic bases include, but are not limited to,triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate,sodium tert-butoxide and potassium tert-butoxide. The inorganic basesinclude, but are not limited to sodium hydride, potassium phosphate,sodium carbonate, potassium carbonate, cesium carbonate, sodiumhydroxide and lithium hydroxide.

The reagents that provide an acidic condition include, but are notlimited to, pyridine hydrobromide, trifluoroacetic acid, formic acid,acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid,preferably pyridine hydrobromide or hydrochloric acid.

The condensing reagent includes, but is not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate,1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateand benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate,preferably 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

The above reaction is preferably carried out in a solvent. The solventused includes, but is not limited to, acetic acid, methanol, ethanol,toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide,1,4-dioxane, water and N,N-dimethylformamide.

A process for preparing a compound of formula (I) of the presentinvention, or a tautomer, mesomer, racemate, enantiomer, diastereomer,or mixture thereof, or a pharmaceutically acceptable salt thereof,comprises the following steps:

wherein:

X is halogen, preferably bromine;

R^(a) is alkyl, preferably methyl;

ring A, L¹, R¹˜R³, R⁵˜R⁶, n and s are as defined in formula (I).

in the first step reaction, a compound of formula (I-1) and a compoundof formula (I-2) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (I-3); or a compound of formula (I-1) and a compound offormula (I-2′) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (I-A);

in the second step reaction, the compound of formula (I-3) is hydrolyzedunder an acidic condition to obtain a compound of (I-A);

in the third step, the compound of formula (I-A) and a compound offormula (AI-B) or a hydrochloride thereof are subjected to acondensation reaction under an alkaline condition, optionally thecondensation product is hydrolyzed under an alkaline condition, toobtain the compound of formula (I).

The reagents that provide an alkaline condition include organic basesand inorganic bases. The organic bases include, but are not limited totriethylamine, N,N-diisopropylethylamine, n-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate,sodium tert-butoxide and potassium tert-butoxide. The inorganic basesinclude, but are not limited to sodium hydride, potassium phosphate,sodium carbonate, potassium carbonate, cesium carbonate, sodiumhydroxide and lithium hydroxide.

The reagents that provide an acidic condition include, but are notlimited to, pyridine hydrobromide, trifluoroacetic acid, formic acid,acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid,preferably pyridine hydrobromide or hydrochloric acid.

The condensing reagent includes, but is not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate,1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateand benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate,preferably 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

The above reaction is preferably carried out in a solvent. The solventused includes, but is not limited to, acetic acid, methanol, ethanol,toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide,1,4-dioxane, water and N,N-dimethylformamide.

A process for preparing a compound of formula (I) of the presentinvention, or a tautomer, mesomer, racemate, enantiomer, diastereomer,or mixture thereof, or a pharmaceutically acceptable salt thereof,comprises the following steps:

wherein:

R^(a) is alkyl, preferably methyl;

R^(b) is a leaving group, preferably methanesulfonyloxy ortrifluoromethanesulfonyloxy;

ring A, L¹, R¹˜R³, R⁵˜R⁶, n and s are as defined in formula (I).

in the first step reaction, a compound of formula (I-1-a) and a compoundof formula (I-2-a) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (I-3);

in the second step reaction, the compound of formula (I-3) is hydrolyzedunder an acidic condition to obtain a compound of (I-A);

in the third step, the compound of formula (I-A) and a compound offormula (AI-B) or a hydrochloride thereof are subjected to acondensation reaction under an alkaline condition, optionally thecondensation product is hydrolyzed under an alkaline condition, toobtain the compound of formula (I).

The reagents that provide an alkaline condition include organic basesand inorganic bases. The organic bases include, but are not limited totriethylamine, N,N-diisopropylethylamine, n-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate,sodium tert-butoxide and potassium tert-butoxide. The inorganic basesinclude, but are not limited to sodium hydride, potassium phosphate,sodium carbonate, potassium carbonate, cesium carbonate, sodiumhydroxide and lithium hydroxide.

The reagents that provide an acidic condition include, but are notlimited to, pyridine hydrobromide, trifluoroacetic acid, formic acid,acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid,preferably pyridine hydrobromide or hydrochloric acid.

The condensing reagent includes, but is not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate,1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateand benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate,preferably 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

The above reaction is preferably carried out in a solvent. The solventused includes, but is not limited to, acetic acid, methanol, ethanol,toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide,1,4-dioxane, water and N,N-dimethylformamide.

A process for preparing a compound of formula (II) of the presentinvention, or a tautomer, mesomer, racemate, enantiomer, diastereomer,or mixture thereof, or a pharmaceutically acceptable salt thereof,comprises the following steps:

wherein:

X is halogen, preferably bromine;

R^(a) is alkyl, preferably methyl;

L¹, R², R³, R⁵˜R⁷ and n are as defined in formula (II).

in the first step reaction, a compound of formula (II-1) and a compoundof formula (I-2) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (II-2); or a compound of formula (II-1) and a compound offormula (I-2′) are subjected to a nucleophilic substitution reactionunder an alkaline condition in an organic solvent to obtain a compoundof formula (II-A);

in the second step reaction, the compound of formula (II-2) ishydrolyzed under an acidic condition to obtain a compound of (II-A);

in the third step, the compound of formula (II-A) and a compound offormula (II-B) or a hydrochloride thereof are subjected to acondensation reaction under an alkaline condition, optionally thecondensation product is hydrolyzed under an alkaline condition, toobtain the compound of formula (II).

The reagents that provide an alkaline condition include organic basesand inorganic bases. The organic bases include, but are not limited totriethylamine, N,N-diisopropylethylamine, n-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate,sodium tert-butoxide and potassium tert-butoxide, preferably lithiumbis(trimethylsilyl)amide. The inorganic bases include, but are notlimited to sodium hydride, potassium phosphate, sodium carbonate,potassium carbonate, cesium carbonate, sodium hydroxide and lithiumhydroxide, preferably potassium carbonate, sodium hydride or lithiumhydroxide.

The reagents that provide an acidic condition include, but are notlimited to, pyridine hydrobromide, trifluoroacetic acid, formic acid,acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid,preferably pyridine hydrobromide or hydrochloric acid.

The condensing agent includes, but is not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate,1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateand benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate,preferably 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

The above reaction is preferably carried out in a solvent. The solventused includes, but is not limited to, acetic acid, methanol, ethanol,toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide,1,4-dioxane, water and N,N-dimethylformamide.

A process for preparing a compound of formula (IV) of the presentinvention, or a tautomer, mesomer, racemate, enantiomer, diastereomer,or mixture thereof, or a pharmaceutically acceptable salt thereof,comprises the following steps:

wherein:

R^(c) is alkyl, preferably methyl;

L¹, R², R³, R⁶, R⁷ and n are as defined in formula (IV).

in the first step reaction, a compound of formula (II-A) and a compoundof formula (IV-1) or a hydrochloride thereof are subjected to acondensation reaction under an alkaline condition to obtain a compoundof formula (IV-2);

in the second step reaction, the compound of formula (IV-2) ishydrolyzed under an acidic condition to obtain a compound of (IV-3);

in the third step reaction, the compound of formula (IV-3) is subjectedto a chiral preparation to obtain a compound of formula (IV).

The reagents that provide an alkaline condition include organic basesand inorganic bases. The organic bases include, but are not limited totriethylamine, N,N-diisopropylethylamine, n-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate,sodium tert-butoxide and potassium tert-butoxide, preferably lithiumbis(trimethylsilyl)amide. The inorganic bases include, but are notlimited to sodium hydride, potassium phosphate, sodium carbonate,potassium carbonate, cesium carbonate, sodium hydroxide and lithiumhydroxide, preferably potassium carbonate, sodium hydride or lithiumhydroxide.

The reagents that provide an acidic condition include, but are notlimited to, pyridine hydrobromide, trifluoroacetic acid, formic acid,acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid,preferably pyridine hydrobromide or hydrochloric acid.

Conditions for the chiral preparation include, but are not limited to, acolumn being Superchiral S-AD (Chiralway), a mobile phase being carbondioxide, ethanol and diethylamine.

The condensing reagent includes, but is not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate,1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateand benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate,preferably 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

The above reaction is preferably carried out in a solvent. The solventused includes, but is not limited to, acetic acid, methanol, ethanol,toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide,1,4-dioxane, water and N,N-dimethylformamide.

As for the compound of each formula involved in the present invention,if a salt form of the compound is obtained during the synthesis, a freeform of the compound can be further obtained by conventionalexperimental means; if the free form of the compound is obtained duringthe synthesis, a salt form of the compound can be further obtained byconventional experimental means.

PREFERRED EMBODIMENTS

The present invention will be further described with reference to thefollowing examples, but the examples should not be considered aslimiting the scope of the invention.

EXAMPLES

The structures of the compounds are identified by nuclear magneticresonance (NMR) and/or mass spectrometry (MS). NMR chemical shifts (δ)are given in 10⁻⁶ (ppm). NMR is determined by a Bruker AVANCE-400machine. The solvents for determination are deuterated-dimethylsulfoxide (DMSO-d₆), deuterated-chloroform (CDCl₃) anddeuterated-methanol (CD₃OD), and the internal standard istetramethylsilane (TMS).

MS is determined by a FINNIGAN LCQAd (ESI) mass spectrometer(manufacturer: Thermo, type: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) analysis is determined onan Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489high pressure liquid chromatography spectrometer.

Chiral HPLC analysis is determined on an Agilent 1260 DAD highperformance liquid chromatography spectrometer.

CombiFlash rapid preparation instrument is Combiflash Rf200 (TELEDYNEISCO).

Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used forthin-layer silica gel chromatography (TLC). The dimension of the silicagel plate used in TLC is 0.15 mm to 0.2 mm, and the dimension of thesilica gel plate used in product purification is 0.4 mm to 0.5 mm.

Yantai Huanghai 200 to 300 mesh silica gel is used as a carrier forcolumn chromatography.

The average kinase inhibition rates and IC₅₀ values are determined by aNovoStar ELISA (BMG Co., Germany).

The known raw materials of the present invention can be prepared byconventional synthesis methods known in the art, or can be purchasedfrom ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company,Accela ChemBio Inc., or Dari chemical Company, etc.

Unless otherwise stated, the reactions are carried out under nitrogenatmosphere or argon atmosphere.

The term “nitrogen atmosphere” or “argon atmosphere” means that areaction flask is equipped with a 1 L nitrogen or argon balloon.

The term “hydrogen atmosphere” means that a reaction flask is equippedwith a 1 L hydrogen balloon.

Pressurized hydrogenation reactions are carried out with a Parr 3916EKXhydrogenation instrument and a QL-500 hydrogen generator or HC2-SShydrogenation instrument.

In hydrogenation reactions, the reaction system is generally vacuumedand filled with hydrogen, and the above operation is repeated threetimes.

CEM Discover-S 908860 type microwave reactor is used in microwavereactions.

Unless otherwise stated, the solution refers to an aqueous solution.

Unless otherwise stated, the reaction temperature in the reactionsrefers to room temperature, ranging from 20° C. to 30° C.

The reaction process is monitored by thin layer chromatography (TLC),and the system of developing solvent, the elution system forpurification of the compounds by column chromatography and thin layerchromatography include: A: dichloromethane and methanol system, B:n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetatesystem, D: acetone, E: dichloromethane and acetone system, F: ethylacetate and dichloromethane system, G: ethyl acetate, dichloromethaneand n-hexane, H: ethyl acetate, dichloromethane and acetone, and I:petroleum ether, ethyl acetate and dichloromethane. The ratio of thevolume of the solvents can be adjusted according to the polarity of thecompounds, and sometimes a little alkaline reagent such as triethylamineor acidic reagent such as acetic acid can be added.

Example 15-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylicacid

Step 1 methyl 2-bromo-4-methoxybutanoate 1b

Methyl 4-methoxybutanoate 1a (1.6 g, 12.1 mmol) was added to 50 mL oftetrahydrofuran, and the resulting solution was cooled to −78° C. in adry ice-acetone bath. Lithium bis(trimethylsilyl)amide (12.7 mL, 12.7mmol) was added slowly. After completion of the addition, the reactionsolution was stirred for 1 hour, and then chlorotrimethylsilane (1.31 g,12.1 mmol) was added. After stirring for 20 minutes, the reactionsolution was added with N-bromosuccinimide (2.15 g, 12.1 mmol) andstirred for 2 hours. The dry ice-acetone bath was removed, and thetemperature of the reaction solution was warmed up to room temperature.Saturated ammonium chloride solution was added to quench the reaction.The reaction solution was extracted with ethyl acetate (50 mL×3). Theorganic phases were combined, washed with water (50 mL) and saturatedsodium chloride solution (50 mL) successively, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography with elution system B to obtain the title compound1b (900 mg, yield: 35.3%).

Step 2 1-(4-chloro-2-(2,5-dimethoxypyridin-4-yl)phenyl)ethanone 1e

1-(2-Bromo-4-chlorophenypethanone 1c (1.27 g, 5.46 mmol),(2,5-dimethoxypyridin-4-yl)boronic acid 1d (1.0 g, 5.46 mmol, preparedby a method disclosed in the patent application “WO2015063093”),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (230 mg,0.32 mmol) and potassium carbonate (2.2 g, 16.38 mmol) were added to 25mL of 1,4-dioxane. After completion of the addition, the reactionsolution was heated to 110° C., stirred for 8 hours, and then cooled toroom temperature naturally. The reaction solution was added with 50 mLof water, and extracted with ethyl acetate (50 mL×3). The organic phaseswere combined, washed with water (50 mL) and saturated sodium chloridesolution (50 mL) successively, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography withelution system B to obtain the title compound 1e (1.0 g, yield: 63.3%).

MS m/z (ESI): 292.3 [M+1]

Step 3 4-(2-acetyl-5-chlorophenyl)-5-methoxypyridin-2(1H)-one 1f

Compound 1e (1.0 g, 3.43 mmol) was added to 10 mL ofN,N-dimethylformamide, and then pyridine hydrobromide (3.30 g, 20.6mmol) was added. After completion of the addition, the reaction solutionwas heated to 105° C., and stirred for 3 hours. The reaction solutionwas added with 50 mL of water and extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with water (50 mL) andsaturated sodium chloride solution (50 mL), dried over anhydrous sodiumsulfated and filtered. The filtrate was concentrated under reducedpressure to obtain the title compound 1f (550 mg, yield: 57.8%).

MS m/z (ESI): 276.3 [M−1]

Step 4 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanoic acid 1g

Compound 1f (350 mg, 1.28 mmol) was added to 10 mL ofN,N-dimethylformamide, and then sodium hydride (153 mg, 3.84 mmol) wasadded slowly in an ice-water bath. After completion of the addition, theice-water bath was removed, and the temperature of the reaction solutionwas warmed up to room temperature naturally. After stirring for 30minutes, the reaction solution was added with compound 1b (350 mg, 1.66mmol), and then stirred for 24 hours. The reaction solution was addedwith 50 mL of water, dropwise added with 1 M hydrochloric acid to adjustthe pH to 3-4, and then extracted with ethyl acetate (50 mL×3). Theorganic phases were combined, washed with water (50 mL) and saturatedsodium chloride (50 mL), dried over anhydrous sodium, and filtrated toremove the desiccant. The filtrate was concentrated under reducedpressure to obtain the crude title compound 1g (360 mg), which wasdirectly used in the next reaction step without purification.

MS m/z (ESI): 394.4 [M+1]

Step 5 ethyl5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate1i

The crude product 1g (180 mg, 0.45 mmol) was added to 10 mL ofN,N-dimethylformamide, followed by addition of2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(313 mg, 0.82 mmol), N,N-diisopropylethylamine (0.22 mL, 1.35 mmol) andethyl 5-amino-1H-indole-2-carboxylate hydrochloride 1h (129 mg, 0.54mmol, prepared by a known method disclosed in “Journal of OrganicChemistry, 2012, 55(2), 766-782”). After completion of the addition, thereaction solution was heated to 50° C., and stirred for 16 hours. Thereaction solution was added with 50 mL of water, and extracted withethyl acetate (50 mL×3). The organic phases were combined, washed withwater (50 mL) and saturated sodium chloride solution (50 mL), dried overanhydrous sodium sulfate, and filtrated to remove the desiccant. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 1i (60 mg, yield: 23.1%).

MS m/z (ESI): 580.4 [M+1]

Step 65-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylicacid 1

Compound 1i (60 mg, 0.103 mmol) was added to 4 mL of a mixed solvent oftetrahydrofuran and methanol (V:V=3:1), followed by addition of 1 Mlithium hydroxide solution (0.83 mL, 0.83 mmol). After completion of theaddition, the reaction solution was stirred for 16 hours, and then thesolvent was evaporated under reduced pressure. The resulting residue wasadded with 10 mL of water and stirred well. The reaction solution wasadded with 1 M hydrochloric acid to adjust the pH to 3-4, and thenextracted with ethyl acetate (50 mL×3). The organic phases werecombined, washed with water (50 mL) and saturated sodium chloride (50mL), dried over anhydrous sodium sulfate and filtrated to remove thedesiccant. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by high performance liquid chromatography(Gilson-281, elution system: acetonitrile, water) to obtain the titlecompound 1 (4 mg, yield: 7.0%).

MS m/z (ESI): 552.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 11.33 (s, 1H), 8.01 (s, 1H),7.89-7.87 (d, 1H), 7.64-7.61 (dd, 1H), 7.47-7.46 (d, 1H), 7.37-7.32 (m,3H), 6.97 (s, 1H), 6.40 (s, 1H), 5.79-5.75 (m, 1H), 3.54 (s, 3H), 3.22(s, 3H), 2.42-2.31 (m, 2H)

Examples 2,3(S)-5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylicacid 2 (R)-5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylic acid 3

Compound 1 (100 mg, 0.18 mmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 μm;mobile phase: mobile phase: ethanol (containing 0.01% trifluoroaceticacid)=100, flow rate: 8 mL/min). The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompounds 2 (10 mg) and 3 (15 mg).

Compound 2:

MS m/z (ESI): 552.5 [M+1]

Chiral HPLC analysis: retention time 8.907 minutes, chiral purity: 98%(chromatographic column: CHIRAL PAK IE, 4.6*150 mm, 5 μm; mobile phase:n-hexane/ethanol/trifluoroacetic acid=40/60/0.06 (v/v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 11.33 (s, 1H), 8.01 (s, 1H),7.89-7.87 (d, 1H), 7.64-7.61 (dd, 1H), 7.47-7.46 (d, 1H), 7.37-7.32 (m,3H), 6.97 (s, 1H), 6.40 (s, 1H), 5.79-5.75 (m, 1H), 3.54 (s, 3H), 3.22(s, 3H), 2.42-2.31 (m, 2H)

Compound 3:

MS m/z (ESI): 552.4 [M+1]

Chiral HPLC analysis: retention time 6.720 minutes, chiral purity: 98%(chromatographic column:CHIRAL PAK IE, 4.6*150 mm, 5 μm; mobile phase:n-hexane/ethanol/trifluoroacetic acid=40/60/0.06 (v/v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 11.33 (s, 1H), 8.01 (s, 1H),7.89-7.87 (d, 1H), 7.64-7.61 (dd, 1H), 7.47-7.46 (d, 1H), 7.37-7.32 (m,3H), 6.97 (s, 1H), 6.40 (s, 1H), 5.79-5.75 (m, 1H), 3.54 (s, 3H), 3.22(s, 3H), 2.42-2.31 (m, 2H)

Example 4 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 4

Step 1 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 4b

Magnesium tert-butoxide (701.62 mg, 7.2 mmol) was dissolved in 250 mL oftetrahydrofuran, and then (R)-2-bromo-3-phenylpropionic acid (1649.77mg, 7.2 mmol, prepared by a known method disclosed in “ChemicalCommunications (Cambridge, United Kingdom), 2014, 50(88), 13489-13491”),potassium tert-butoxide (404.07 mg, 3.6 mmol) and the crude compound 1f(1000 mg, 3.6 mmol) were added. The reaction solution was reacted for 16hours at 60° C., cooled to room temperature, dropwise added with 1 Mhydrochloric acid to adjust the pH to 3-4, and extracted with ethylacetate (50 mL×3). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by highperformance liquid chromatography (Gilson-281, elution system:acetonitrile, water) to obtain the title compound 4b (350 mg, yield:20.5%).

MS m/z (ESI): 426.4 [M+1]

Step 2 methyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 4d

Compound 4b (350 mg, 0.82 mmol), methyl 4-aminobenzoate 4c (39.23 mg,0.26 mmol, prepared by a known method disclosed in “ChemicalCommunications (Cambridge, United Kingdom), 2015, 51(58), 11705-11708”)and N,N-diisopropylethylamine (0.57 mL, 3.29 mmol) were successivelydissolved in 30 mL of ethyl acetate, followed by dropwise addition of asolution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 1569 mg, 2.47 mmol). After completion of theaddition, the reaction was warmed up to 60° C., and stirred for 2 hours.The reaction solution was cooled to room temperature, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography with elution system A to obtain the title compound4d (140 mg, yield: 28.9%).

MS m/z (ESI): 559.5 [M+1]

Step 3 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 4

Compound 4d (120 mg, 0.21 mmol) was dissolved in 4 mL of a mixed solventof tetrahydrofuran and methanol (V/V=3:1), followed by addition of 1.28mL of 1M lithium hydroxide solution. After completion of the addition,the reaction solution was stirred for 16 hours. The reaction solutionwas dropwise added with 10% hydrochloric acid to adjust the pH to 3-4,and extracted with ethyl acetate (50 mL×2). The organic phases werecombined and concentrated under reduced pressure. The resulting residuewas purified by high performance liquid chromatography (Gilson-281,elution system: acetonitrile, water) to obtain the title compound 4 (50mg, yield: 42.7%).

MS m/z (ESI): 545.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H),7.83-7.81 (d, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.62-7.59 (dd, 1H), 7.43(s, 1H) 7.38 (s, 1H), 7.30-7.25 (m, 4H), 7.21-7.17 (m, 1H), 6.31 (s,1H), 6.05-6.01 (m, 1H), 3.54 (s, 3H), 3.49-3.44 (m, 2H), 2.37 (s, 3H).

Examples 5, 6(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 5(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 6

Compound 4 (900 mg, 1.62 mmol) was separated chirally (separationcondition: chiral preparative column Superchiral S-AD (Chiralway), 2 cmI.D.*25 cm Length, 5 m; mobile phase: carbondioxide:ethanol:diethylamine=60:40:0.05, flow rate: 50 g/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 5 (421 mg) and 6 (405 mg).

Compound 5:

MS m/z (ESI): 545.4 [M+1];

Chiral HPLC analysis: retention time 4.138 minutes, chiral purity: 98%(chromatographic column: Superchiral S-AD (Chiralway), 2 cm I.D.*25 cmLength, 5 μm; mobile phase: ethanol/n-hexane/trifluoroaceticacid=50/50/0.05 (v/v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H),7.83-7.81 (d, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.62-7.59 (dd, 1H), 7.43(s, 1H) 7.38 (s, 1H), 7.30-7.25 (m, 4H), 7.21-7.17 (m, 1H), 8.31 (s,1H), 6.05-6.01 (m, 1H), 3.54 (s, 3H), 3.49-3.44 (m, 2H), 2.37 (s, 3H)

Compound 6:

MS m/z (ESI): 545.4 [M+1]

Chiral HPLC analysis: retention time 1.475 minutes, (chromatographiccolumn: Superchiral S-AD (Chiralway), 2 cm I.D.*25 cm Length, 5 μm;mobile phase: ethanol/n-hexane/trifluoroacetic acid=50/50/0.05 (v/v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H),7.83-7.81 (d, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.62-7.59 (dd, 1H), 7.43(s, 1H) 7.38 (s, 1H), 7.30-7.25 (m, 4H), 7.21-7.17 (m, 1H), 8.31 (s,1H), 6.05-6.01 (m, 1H), 3.54 (s, 3H), 3.49-3.44 (m, 2H), 2.37 (s, 3H)

Example 7 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiophen-3-yl) propanamido)benzoic acid 7

Step 1 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)acetate7b

Compound 1f (3.4 g, 12.24 mmol), cesium carbonate (11937.34 mg, 36.73mmol) and tert-butyl 2-bromoacetate 7a (3.58 g, 18.37 mmol, prepared bya known method disclosed in “Chemical Communications (Cambridge, UnitedKingdom), 2012, 48(22), 2803-2805”) were successively dissolved in 40 mLN,N-dimethylformamide. After completion of the addition, the reactionsolution was warmed up to 65° C. and stirred for 2 hours. The reactionsolution was cooled to room temperature, added with 50 mL of water,extracted with ethyl acetate (50 mL×3), and the organic phase was washedwith saturated sodium chloride solution (50 mL×3). The organic phaseswere combined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem I to obtain the title compound 7b (3.2 g, yield: 65.4%).

MS m/z (ESI): 392.1[M+1]

Step 2 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2f)-yl)-3-(thiophen-3-yl)propanoate 7d

Compound 7b (100 mg, 0.26 mmol) and 3-(bromomethyl)thiophene 7c (90.37mg, 0.51 mmol, prepared by a known method disclosed in “Journal ofOrganic Chemistry, 2016, 81(22), 11035-11042”) were successivelydissolved in 10 mL of tetrahydrofuran. The reaction solution was cooledto −78° C., dropwise added with lithium diisopropylamide solution (1.53mL, 1.02 mmol), and reacted for 2 hours. 1 mL of water was added slowly,and the temperature of the reaction solution was warmed up to roomtemperature naturally. The reaction solution was added with 10 mL ofwater, and then extracted with ethyl acetate (20 mL×3). The organicphase was washed with saturated sodium chloride solution (20 mL×2), andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography withelution system B to obtain the title compound 7d (84 mg, yield: 64.1%).

MS m/z (ESI): 488.4[M+1]

Step 32-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiophen-3-yl)propanoicacid 7e

Compound 7d (80 mg, 0.16 mmol) was dissolved in 4 mL of dichloromethane.The reaction solution was added with trifluoroacetic acid (0.5 mL, 0.78mmol) and stirred for 5 hours. The reaction solution was evaporatedunder reduced pressure to obtain the crude title compound 7e (68 mg),which was directly used in the next reaction step without purification.

MS m/z (ESI): 432.3 [M+1]

Step 4 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiophen-3-yl)propanamido)benzoate 7f

The crude compound 7e (67 mg, 0.16 mmol) and compound 4 (30.48 mg, 0.20mmol) were dissolved in 6 mL of ethyl acetate, followed by successiveaddition of 0.5 mL of pyridine and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide(197.44 mg, 0.62 mmol). After completion of the addition, the reactionwas warmed up to 70° C., and stirred for 1.5 hours. The reactionsolution was added with 15 mL of water, extracted with ethyl acetate (15mL×2), washed with saturated sodium chloride solution (15 mL×2), driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography with elution system A toobtain the title compound 7f (80 mg), yield: 86.7%.

MS m/z (ESI): 565.5[M+1];

Step 5 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiophen-3-yl) propanamido)benzoic acid 7

Compound 7f (80 mg, 0.13 mmol) was dissolved in 3 mL of tetrahydrofuran,followed by addition of sodium hydroxide solution (1 N, 0.67 mL). Aftercompletion of the addition, the reaction solution was stirred for 12hours, followed by addition of sodium hydroxide solution (1 N, 0.67 mL).The reaction solution was warmed up to 35° C., and stirred for 16 hours.The organic solvent was evaporated under reduced pressure. 15 mL ofwater were added, and then the reaction solution was added with 3 Nhydrochloric acid to adjust the pH to 4-5, and filtered. The filter cakewas collected, and the resulting residue was purified by silica gelcolumn chromatography with elution system A to obtain the title compound7 (50 mg, yield: 64.8%).

MS m/z (ESI): 551.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 10.81 (s, 1H), 7.92 (d, 2H),7.84 (d, 1H), 7.75 (d, 2H), 7.62 (dd, 1H), 7.45 (dd, 1H), 7.40 (d, 2H),7.22 (d, 1H), 7.01 (d, 1H), 6.34 (s, 1H), 5.99-5.95 (m, 1H), 3.58-3.52(m, 1H), 3.53 (s, 3H), 3.46-3.41 (m, 1H), 2.41 (s, 3H)

Example 84-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 8

Step 1 1-(2-bromo-4-chlorophenyl)propan-1-one 8c

2-Bromo-4-chloro-1-iodobenzene 8a (1.0 g, 3.15 mmol, prepared by a knownmethod disclosed in “Angewandte Chemie, International Edition, 2010,49(46), 8729-8732”) was dissolved in 1 mL of tetrahydrofuran. Thereaction solution was cooled to −20° C., added with isopropylmagnesiumchloride (421.15 mg, 4.10 mmol), and pre-reacted for 1 hour. Propionylchloride 8b (378.89 mg, 4.10 mmol), lithium chloride (11.42 mg, 189.00μmol), cuprous chloride (9.36 mg, 94.50 μmol) and aluminum trichloride(12.61 mg, 94.50 μmol) were added to 1 mL of tetrahydrofuran, andstirred well at room temperature. The pre-reacted reaction solution wasdropwise added to the above mixture, and reacted for 2 hours at roomtemperature. The reaction solution was added with 20 mL of saturatedammonium chloride solution to quench the reaction, and extracted withdichloromethane (20 mL×3). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified byCombiFlash rapid preparation instrument with elution system B to obtainthe title compound 8c (640 mg, yield: 82.0%).

Step 2 1-(4-chloro-2-(2,5-dimethoxypyridin-4-yl)phenyl)propan-1-one 8d

Compound 8c (640 mg, 2.59 mmol), compound 1d (520.41 mg, 2.84 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (191.8 mg,0.259 mmol) and sodium carbonate (822.16 mg, 7.76 mmol) were added to amixed solvent of 20 mL of 1,4-dioxane and 4 mL of water. Aftercompletion of the addition, the reaction solution was warmed up to 85°C., and stirred for 16 hours. After cooling to room temperature, thereaction solution was added with 20 mL of water, and extracted withethyl acetate (20 mL×3). The organic phases were combined, washed withwater (30 mL) and saturated sodium chloride solution (30 mL)successively, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 8d (600 mg, yield: 75.9%).

MS m/z (ESI): 306.0 [M+1]

Step 3 4-(5-chloro-2-propionylphenyl)-5-methoxypyridin-2(1H)-one 8e

Compound 8d (600 mg, 1.96 mmol) was added to 10 mL ofN,N-dimethylformamide, followed by addition of pyridine hydrobromide(1.51 g, 9.81 mmol). After completion of the addition, the reactionsolution was heated to 100° C., and stirred for 3 hours. The reactionsolution was cooled to room temperature, and concentrated under reducedpressure to remove the organic solvent. The resulting residue was addedwith 30 mL of water, and extracted with dichloromethane (20 mL×3). Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to obtainthe title compound 8e (550 mg), which was directly used in the nextreaction step without purification.

Step 4 tert-butyl2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)acetate 8f

The crude compound 8e (550 mg, 1.89 mmol), cesium carbonate (1.84 g,5.67 mmol) and compound 7a (551.61 mg, 2.83 mmol) were dissolved in 10mL of N,N-dimethylformamide. After completion of the addition, thereaction solution was warmed up to 65° C., and stirred for 2 hours.After cooling to room temperature, the reaction solution was added with30 mL of water, and extracted with ethyl acetate (30 mL×3). The organicphases were combined, washed with saturated sodium chloride solution (30mL×3), dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure, and the resulting residue waspurified by CombiFlash rapid preparation instrument with elution systemB to obtain the title compound 8f (350 mg, yield: 51.0%).

MS m/z (ESI): 405.4 [M+1]

Step 5 tert-butyl2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate8h

Compound 8f (122 mg, 302.37 μmol) was dissolved in 10 mL oftetrahydrofuran. The reaction solution was cooled to −78° C., added with8g (103.43 mg, 604.74 μmol), followed by addition of a solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.21 mL, 1.21mmol), and reacted for 2 hours. After warming up to room temperature,the reaction solution was added with 10 mL of water and extracted withethyl acetate (20 mL×3). The organic phases were combined, washed withsaturated sodium chloride solution (20 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography with elution system B to obtain the title compound8h (75 mg, yield: 50.0%).

MS m/z (ESI): 496.2 [M+1]

Step 6 2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 8i

Compound 8h (75 mg, 0.15 mmol) was dissolved in 4 mL of dichloromethane,followed by dropwise addition of trifluoroacetic acid (0.5 mL). Thereaction solution was stirred for 5 hours and concentrated under reducedpressure to obtain the crude title compound 8i (70 mg), which wasdirectly used in the next reaction step without purification.

MS m/z (ESI): 439.9 [M+1]

Step 74-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 8

The crude compound 8i (70 mg, 159.13 μmol) and 4-aminobenzoic acid 8j(32.73 mg, 237.70 μmol, prepared by a known method disclosed in“Angewandte Chemie—International Edition, 2012, 51(34), 8564-8567”) wasdissolved in 20 mL of ethyl acetate, followed by successive addition oftriethylamine (64.41 mg, 636.53 μmol) and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 303.80 mg, 477.39 μmol). After completion of theaddition, to the reaction solution was warmed up to 60° C., and stirredfor 2 hours. After cooling to room temperature, the reaction solutionwas added with 15 mL of water, extracted with ethyl acetate (15 mL×2),washed with saturated sodium chloride (15 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography with elution system A to obtain the title compound8 (30 mg, yield: 35.7%).

MS m/z (ESI): 559.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 8.10 (d, 2H), 7.86 (d, 2H), 7.70(d, 1H), 7.51-7.24 (m, 8H), 6.64 (s, 1H), 6.26 (s, 1H), 3.67-3.62 (m,4H), 3.33-3.29 (m, 1H), 2.86 (s, 2H), 1.18-0.92 (m, 3H).

Examples 9, 10(S)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 9 (R)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 10

Compound 8 (1 g, 1.79 mmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE 20*250 mm 5 μm;mobile phase: n-hexane:ethanol=55:45, flow rate: 7 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 9 (300 mg) and compound 10 (400mg).

Compound 9:

MS m/z (ESI): 559.5 [M+1]

Chiral HPLC analysis: retention time 11.267 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol/n-hexane=50/50 (v/v)).

¹H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1H), 8.10 (d, 2H), 7.85 (d, 2H), 7.69(d, 1H), 7.48 (d, 1H), 7.40 (s, 7H), 6.62 (s, 1H), 6.22 (s, 1H), 3.65(s, 3H), 3.60 (s, 1H), 3.31 (s, 1H), 2.85 (s, 2H), 1.15 (s, 3H).

Compound 10:

MS m/z (ESI): 559.5 [M+1]

Chiral HPLC analysis: retention time 4.836 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol/n-hexane=50/50 (v/v)).

¹H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1H), 8.10 (d, 2H), 7.85 (d, 2H), 7.69(d, 1H), 7.48 (d, 1H), 7.40 (s, 7H), 6.62 (s, 1H), 6.22 (s, 1H), 3.65(s, 3H), 3.60 (s, 1H), 3.31 (s, 1H), 2.85 (s, 2H), 1.15 (s, 3H).

Example 11(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide11

Compound 5 (54 mg, 99.09 μmol) was dissolved in 5 mL ofN,N-dimethylformamide, and then ammonium carbonate (64.03 mg, 495.43μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (112.96 mg, 297.26 μmol) were added. The reactionsolution was stirred for 16 hours at room temperature, added with 20 mLof saturated sodium bicarbonate solution, and extracted with ethylacetate (50 mL×2). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by theelution system A to obtain the title compound 11 (40 mg, yield: 74.2%).

MS m/z (ESI): 544.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.87-7.82 (m, 3H), 7.70-7.69 (m, 1H),7.68-7.66 (m, 1H), 7.56-7.54 (dd, 1H), 7.36 (s, 1H), 7.32-7.31 (d, 1H),7.29-7.25 (m, 4H), 7.24-7.19 (m, 1H), 6.41 (s, 1H), 5.89-5.85 (m, 1H),3.65-3.60 (m, 1H), 3.59 (s, 3H), 3.50-3.45 (m, 1H), 2.46 (s, 3H).

Example 12 methyl(S)-(4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)phenyl)carbamate12

Compound 5 (100 mg, 183.83 μmol) was dissolved in 8 mL of toluene,followed by successive addition of triethylamine (65.1 mg, 643.39 μmol),diphenyl azidophosphate (60.71 mg, 220.59 μmol) and methanol (58.9 mg,1.84 mmol). The reaction solution was warmed up to 100° C., and stirredfor 2 hours. The reaction solution was cooled to room temperature, andconcentrated under reduced pressure to remove the solvent. The resultingresidue was added with 15 mL of saturated sodium bicarbonate solution,and extracted with ethyl acetate (50 mL×2). The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified Silica gel column chromatography with elutionsystem A to obtain the title compound 12 (75 mg, yield: 71.2%).

MS m/z (ESI): 574.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (d, 1H), 7.48-7.46 (d, 3H),7.29-7.21 (m, 8H), 7.15-7.10 (m, 1H), 6.61-6.50 (m, 2H), 5.95-5.85 (m,1H), 3.76 (s, 3H), 3.65-3.60 (m, 1H), 3.59 (s, 3H), 3.30-3.20 (m, 1H),2.42 (s, 3H).

Example 13(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N-methylbenzamide13

Compound 5 (70 mg, 128.44 μmol) was dissolved in 5 mLN,N-dimethylformamide, and then methylamine (11.97 mg, 385.33 μmol),N,N-diisopropylethylamine (66.4 mg, 513.78 μmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (97.62 mg, 256.89 μmol) was added successively. Thereaction solution was stirred for 16 hours at room temperature, addedwith 50 mL of ethyl acetate, and washed with water (30 mL×2). Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by high performance liquid chromatography(Waters 2767-SQ detecor2, elution system: acetonitrile, water) to obtainthe title compound 13 (45 mg, yield: 62.8%).

MS m/z (ESI): 558.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.39-8.34 (m, 1H), 7.84-7.82(m, 3H), 7.71 (d, 2H), 7.62 (dd, 1H), 7.44 (s, 1H), 7.38 (s, 1H),7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 6.31 (s, 1H), 6.04-6.01 (m, 1H),3.54 (s, 3H), 3.49-3.39 (m, 2H), 2.77 (d, 3H), 2.38 (s, 3H).

Examples 14, 15 (R)-((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 14 (S)-((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 15

Step 1 ((ethoxycarbonyl)oxy)methyl4-((tert-butoxycarbonyl)amino)benzoate 14c

4-((tert-butoxycarbonyl)amino)benzoic acid 14a (4 g, 16.86 mmol,prepared by a known method disclosed in “Journal of Medicinal Chemistry,2016, 59(22), 10299-10314”), potassium iodide (2.24 g, 13.49 mmol) andpotassium carbonate (2.33 g, 16.86 mmol) were dissolved in 50 mL ofN,N-dimethylformamide, followed by addition of chloromethyl ethylcarbonate 14b (3.5 g, 25.29 mmol, prepared by a known method disclosedin “Tetrahedron Letters, 2007, 48(1), 109-112”) under argon atmosphere.After completion of the addition, the reaction solution was warmed up to50° C., stirred for 16 hours and cooled to room temperature. Thereaction solution was added with 100 mL of ice water, and extracted withethyl acetate (60 mL×3). The organic phases were combined, washed with25 mL of saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography with elution system C to obtain the title compound 14c(5.3 g, yield: 88.0%).

MS m/z (ESI): 340.5 [M+1]

Step 2 ((ethoxycarbonyl)oxy)methyl 4-aminobenzoate hydrochloride 14d

A solution of hydrogen chloride in 1,4-dioxane (13.3 mL, 66.52 mmol) wasadded to 13 mL of tetrahydrofuran, followed by addition of compound 14c(2.7 g, 7.56 mmol). After completion of the addition, the reactionsolution was warmed up to 50° C., stirred for 5 hours, cooled to roomtemperature, and concentrated under reduced pressure to remove thesolvent. The resulting residue was added with 20 mL of a mixed solventof ethyl acetate and hexane (V/V=1:9), stirred, and filtered. The filtercake was collected to obtain the crude title compound 14d (2 g), whichwas directly used in the next reaction step without purification.

MS m/z (ESI): 240.4 [M+1]

Step 3 ((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 14e

Compound 4b (250 mg, 0.59 mmol) was dissolved in 50 mL of ethyl acetate,followed by addition of N,N-diisopropylethylamine (303.48 mg, 2.35mmol), the crude compound 14d (178.03 mg, 0.65 mmol) and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 747.14 mg, 1.17 mmol). After completion of theaddition, the reaction solution was warmed up to 60° C., and stirred for2 hours. After cooling to room temperature, the reaction solution wasadded with 25 mL of saturated sodium bicarbonate solution and extractedwith ethyl acetate (50 mL×2). The organic phases were combined, driedover anhydrous sodium bicarbonate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by the high performance liquid chromatography (Gilson-281,elution system: acetonitrile, water) to obtain the title compound 14e(230 mg, yield: 60.6%).

MS m/z (ESI): 647.5 [M+1]

Step 4 (R)-((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 14 (S)-((ethoxycarbonyl)oxy)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 15

Compound 14e (230 mg, 0.36 mmol) was separated chirally (separationconditions: chromatographic column: Superchiral S-AD (Chiralway), 2 cmI.D.*25 cm Length, 5 μm; mobile phase: carbon dioxide:isopropanol=60:40,flow rate: 50 g/min). The corresponding fractions were collected andconcentrated under reduced pressure to obtain the title compound 14 (84mg) and compound 15 (76 mg).

Compound 14:

MS m/z (ESI): 647.5 [M+1]

Chiral HPLC analysis: retention time 5.297 minutes, (chromatographiccolumn: CHIRAL PAK IE, 4.6*150 mm, 5 m; flow rate: 1 mL/min; mobilephase: ethanol).

¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H),7.70-7.69 (d, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.48-7.46 (dd, 1H),7.30-7.27 (m, 4H), 7.26-7.22 (m, 2H), 7.05-7.02 (m, 1H), 6.57 (s, 1H),5.99 (s, 2H), 5.95-5.85 (m, 1H), 4.29-4.24 (m, 2H), 3.75-3.65 (m, 1H),3.59 (s, 3H), 3.35-3.25 (m, 1H), 2.44 (s, 3H), 1.35-1.31 (m, 3H).

Compound 15:

MS m/z (ESI): 647.5 [M+1]

Chiral HPLC analysis: retention time 8.442 minutes, (chromatographiccolumn: CHIRAL PAK IE, 4.6*150 mm, 5 m; flow rate: 1 mL/min; mobilephase: ethanol).

¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H),7.70-7.69 (d, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.48-7.46 (dd, 1H),7.30-7.27 (m, 4H), 7.26-7.22 (m, 2H), 7.05-7.02 (m, 1H), 6.57 (s, 1H),5.99 (s, 2H), 5.95-5.85 (m, 1H), 4.29-4.24 (m, 2H), 3.75-3.65 (m, 1H),3.59 (s, 3H), 3.35-3.25 (m, 1H), 2.44 (s, 3H), 1.35-1.31 (m, 3H).

Example 164-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-(cyclopropanecarboxamido)phenyl)propanamido)benzoicacid 16

Step 1 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-nitrophenyl)propanoate16b

Compound 7b (150 mg, 0.38 mmol) and 1-(bromomethyl)-4-nitrobenzene 16a(165.39 mg, 0.77 mmol, prepared by a known method disclosed in“Angewandte Chemie—International Edition, 2014, 53(50), 13835-13839”)were successively dissolved in 10 mL of tetrahydrofuran. The reactionsolution was cooled to −78° C., dropwise added with lithiumbis(trimethylsilyl)amide, and reacted for 2 hours. The reaction solutionwas added with 1 mL of water to quench the reaction, warmed up to roomtemperature naturally, added with 10 mL of water, and extracted withethyl acetate (20 mL×2). The organic phases were combined, washed withsaturated sodium chloride solution (20 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography with elution system B to obtain the title compound16b (180 mg, yield: 80.3%).

MS m/z (ESI): 527.4 [M+1]

Step 22-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-nitrophenyl)propanoicacid 16c

Compound 16b (180 mg, 0.34 mmol) was dissolved in 5 mL ofdichloromethane, and then trifluoroacetic acid (0.5 mL) was dropwiseadded. The reaction solution was stirred for 5 hours, and thenconcentrated under reduced pressure to obtain the crude title compound16c (166 mg), which was directly used in the next reaction step withoutpurification.

MS m/z (ESI): 471.4 [M+1]

Step 3 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-nitrophenyl)propanamido)benzoate 16d

The crude compound 16c (161 mg, 0.34 mmol) and compound 4c (67.19 mg,0.44 mmol) were dissolved in 6 mL of ethyl acetate, followed bysuccessive addition of 0.5 mL of pyridine and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 870.36 mg, 1.37 mmol). After completion of theaddition, the reaction solution was warmed up to 70° C., and stirred for1.5 hours. After cooling to room temperature, the reaction solution wasadded with 15 mL of water and extracted with ethyl acetate (15 mL×2).The organic phases were combined, washed with saturated sodium chloride(15 mL×2), dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem A to obtain the title compound 16d (130 mg, yield: 53.5%).

MS m/z (ESI): 604.4 [M+1]

Step 4 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-aminophenyl)propanamido)benzoate16e

The crude compound 16d (70 mg, 115.89 μmol) was dissolved in 8 mL oftetrahydrofuran, and then platinum dioxide (5.26 mg, 23.18 μmol) wasadded. The reaction system was purged with hydrogen twice. The reactionsolution was stirred for 2.5 hours at room temperature, and thenfiltered. The filtrate was concentrated under reduced pressure to obtainthe title compound 16e (66 mg), which was directly used in the nextreaction step without purification.

Step 5 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-(cyclopropanecarboxamido)phenyl)propanamido)benzoate16g

The crude compound 16e (66 mg, 114.98 μmol) and triethylamine (290.87mg, 2.87 mmol) were dissolved in 8 mL of tetrahydrofuran, and thencyclopropanoyl chloride (240.38 mg, 2.30 mmol) was added. The reactionsolution was stirred for 16 hours, and then concentrated under reducedpressure. The resulting residue was added with 15 mL of water, andextracted with ethyl acetate (15 mL×2). The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem A to obtain the title compound 16g (40 mg, yield: 54.2%).

MS m/z (ESI): 642.1 [M+1]

Step 64-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-(cyclopropanecarboxamido)phenyl)propanamido)benzoicacid 16

Compound 16g (40 mg, 62.3 μmol) was dissolved in 3 mL of methanol, andthen sodium bicarbonate (12.46 mg, 311.48 μmol) was added. The reactionsolution was warmed up to 50° C. and stirred for 5 hours. After coolingto room temperature, the reaction solution was added with 15 mL ofwater, followed by addition of 3M hydrochloric acid to adjust the pH to5, and extracted with ethyl acetate (20 mL×2). The organic phases werecombined, washed with saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by high performance liquid chromatography (Waters 2767-SQdetecor2, elution system: acetonitrile, water) to obtain the titlecompound 16 (16 mg, yield: 40.9%).

MS m/z (ESI): 628.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H), 10.12 (s, 1H), 7.92 (d, 2H),7.83 (d, 1H), 7.76 (d, 2H), 7.61 (dd, 1H), 7.48 (d, 2H), 7.41 (d, 2H),7.18 (d, 2H), 6.30 (s, 1H), 6.00-5.96 (m, 1H), 3.55 (s, 3H), 3.42-3.36(m, 2H), 2.39 (s, 3H), 1.76-1.70 (m, 1H), 0.76-0.74 (m, 4H).

Example 174-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4′-cyano-2′-methyl-[1,1′-biphenyl]-4-yl)propanamido)benzoicacid 17

Step 1 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-bromophenyl)propanoate 17b

Compound 7b (150 mg, 0.38 mmol) and 1-bromo-4-(bromomethyl)benzene 17a(191.35 mg, 0.77 mmol, prepared by a known method disclosed in“Tetrahedron Letters, 2016, 57(2), 168-171”) were dissolved in 10 mL oftetrahydrofuran. After cooling to −78° C., the reaction solution wasdropwise added with lithium bis(trimethylsilyl)amide solution (1.53 mL,1.53 mmol) and reacted for 2 hours. The reaction solution was added with1 mL of water to quench the reaction, warmed up to room temperaturenaturally, added with 10 mL of water, and extracted with ethyl acetate(20 mL×2). The organic phases were combined, washed with saturatedsodium chloride solution (20 mL×2), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure, andthe resulting residue was purified by silica gel column chromatographywith elution system B to obtain the title compound 17b (180 mg, yield:79.6%).

MS m/z (ESI): 562.3 [M+1]

Step 2 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-bromophenyl) propanoic acid 17c

Compound 17b (180 mg, 0.30 mmol) was dissolved in 5 mL ofdichloromethane, and then trifluoroacetic acid (0.5 mL) was added. Thereaction solution was stirred for 5 hours, and then concentrated underreduced pressure to obtain the crude title compound 17c (160 mg), whichwas directly used in the next reaction step without purification.

MS m/z (ESI): 506.3 [M+1]

Step 3 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-bromophenyl)propanamido)benzoate17d

The crude compound 17c (154 mg, 0.31 mmol) and compound 4c (59.95 mg,0.40 mmol) were dissolved in 6 mL of ethyl acetate, followed bysuccessive addition of 0.5 mL of pyridine and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 776.60 mg, 1.22 mmol). After completion of theaddition, the reaction solution was warmed up to 70° C., and stirred for1.5 hours. The reaction solution was added with 15 mL of water andextracted with ethyl acetate (15 mL×2). The organic phases werecombined, washed with saturated sodium chloride solution (15 mL×2),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography with elution system A toobtain the title compound 17d (180 mg, yield: 90.6%).

MS m/z (ESI): 639.3 [M+1]

Step 4 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4′-cyano-2′-methyl-[1,1′-biphenyl]-4-yl)propanamido)benzoate17f

Compound 17d (180 mg, 0.28 mmol), (4-cyano-2-methylphenyl)boronic acid17e (90.84 mg, 0.56 mmol, prepared by a known method disclosed in“Tetrahedron, 2011, 67(52), 10082-10088”),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (20.65 mg,0.03 mmol) and sodium carbonate (89.73 mg, 0.85 mmol) were added to amixed solvent of toluene (8 mL), ethanol (3 mL) and water (1 mL). Aftercompletion of the addition, the reaction solution was warmed up to 85°C., and stirred for 16 hours. After cooling to room temperature, thereaction solution was added with 15 mL of water, and extracted withethyl acetate (20 mL×2). The organic phases were combined, washed withsaturated sodium chloride solution (20 mL×2), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography with elution system A to obtain the title compound 17f(200 mg, yield: 31.5%).

MS m/z (ESI): 674.5 [M+1]

Step 54-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4′-cyano-2′-methyl-[1,1′-biphenyl]-4-yl)propanamido)benzoicacid 17

Compound 17f (200 mg, 0.297 mmol) was dissolved in a mixed solvent of 2mL of methanol and 2 mL of tetrahydrofuran, and then lithium hydroxide(29.9 mg, 0.71 mmol) was added. The reaction solution was stirred for 60hours. The reaction solution was added with 15 mL of water, followed bydropwise addition of 3M hydrochloric acid to adjust the pH to 4-5, andextracted with ethyl acetate (20 mL×2). The organic phases werecombined, washed with saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by high performance liquid chromatography (Waters 2767-SQdetecor2, elution system: acetonitrile, water) to obtain the titlecompound 17 (10 mg, yield: 16.2%).

MS m/z (ESI): 660.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.92 (d, 2H), 7.83 (d, 1H),7.78-7.74 (m, 3H), 7.70 (dd, 1H), 7.61 (dd, 1H), 7.43-7.35 (m, 5H), 7.29(d, 2H), 6.33 (s, 1H), 6.06-6.02 (m, 1H), 3.61-3.50 (m, 2H), 3.54 (s,3H), 2.38 (s, 3H), 2.22 (s, 3H).

Example 182-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide18

Compound 4b (90 mg, 211.34 μmol), 2-methyl-2H-indazol-5-amine 18a (34.21mg, 232.47 μmol, prepared by a known method disclosed in “Journal of theAmerican Chemical Society, 2016, 138(14), 4730-4738”) andN,N-diisopropylethylamine (273.14 mg, 2.11 mmol) were added to 15 mL ofethyl acetate, followed by addition of a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 537.94 mg, 845.36 μmol). After completion of theaddition, the reaction solution was warmed up to 75° C., and stirred for2 hours. After cooling to room temperature, the reaction solution wasadded with 30 mL of water, followed by addition of 3M hydrochloric acidto adjust the pH to 5, and two phases were separated. The water phasewas extracted with ethyl acetate (30 mL×2). The organic phases werecombined, washed with saturated sodium chloride solution (35 mL×2),dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography with elution system A toobtain the title compound 18 (80 mg, yield: 68.2%).

MS m/z (ESI): 555.0 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H),7.83 (d, 1H), 7.61 (dd, 1H), 7.56 (d, 1H), 7.49 (s, 1H), 7.38 (s, 1H),7.31-7.25 (m, 5H), 7.21-7.17 (m, 1H), 6.31 (s, 1H), 6.07-6.03 (m, 1H),4.13 (s, 3H), 3.55 (s, 3H), 3.46 (d, 2H), 2.38 (s, 3H).

Examples 19, 20(R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide19(S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide20

Compound 18 (75 mg, 135.13 μmol) was separated chirally (separationconditions: chiral preparative column Lux Cellulose-1 OD 21.2*250 mm 5m; mobile phase: n-hexane:ethanol=60:40, flow rate: 8 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 19 (28 mg) and compound 20 (27mg).

Compound 19:

MS m/z (ESI): 555.5 [M+1]

Chiral HPLC analysis: retention time 5.816 minutes, chiral purity: 100%(chromatographic column: Lux Cellulose-1 OD 4.6*150 mm 5 μm (with aguard column): mobile phase: ethanol/hexane=30/70 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H),7.82 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.48 (s, 1H), 7.38 (s, 1H),7.31-7.25 (m, 5H), 7.21-7.17 (m, 1H), 6.31 (s, 1H), 6.07-6.03 (m, 1H),4.13 (s, 3H), 3.55 (s, 3H), 3.45 (d, 2H), 2.38 (s, 3H).

Compound 20:

MS m/z (ESI): 555.5 [M+1]

Chiral HPLC analysis: retention time 10.287 minutes, chiral purity: 100%(chromatographic column: Lux Cellulose-1 OD 4.6*150 mm 5 μm (with aguard column): mobile phase: ethanol/hexane=30/70 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H),7.83 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.48 (s, 1H), 7.38 (s, 1H),7.31-7.25 (m, 5H), 7.21-7.17 (m, 1H), 6.31 (s, 1H), 6.07-6.03 (m, 1H),4.13 (s, 3H), 3.55 (s, 3H), 3.45 (d, 2H), 2.38 (s, 3H).

Example 21 4-(2-(4-(2-butyryl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropan amido)benzoic acid 21

In accordance with the synthetic route of Example 8, the startingcompound 8b was replaced with n-butyryl chloride, accordingly, the titlecompound 21 (95 mg) was prepared.

MS m/z (ESI): 573.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 10.00 (s, 1H), 8.10-8.00 (d, 2H), 7.83-7.80(d, 2H), 7.69-7.67 (d, 1H), 7.50-7.45 (dd, 1H), 7.34-7.25 (m, 7H), 6.65(s, 1H), 6.29-6.19 (s, 3H), 3.64-3.58 (m, 4H), 3.30-3.22 (m, 1H),2.80-2.70 (m, 2H), 1.70-1.60 (m, 2H), 0.94-0.89 (m, 3H).

Example 224-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-2-fluorobenzamide22

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 4-amino-2-fluorobenzamide (prepared by amethod disclosed in the patent application “WO 2013146963”),accordingly, the title compound 22 (30 mg) was prepared.

MS m/z (ESI): 562.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 7.80 (d, 1H), 7.67-7.52 (m,5H), 7.38-7.37 (m, 3H), 7.26-7.25 (m, 4H), 7.05-7.04 (m, 1H), 6.29 (s,1H), 5.96-5.93 (m, 1H), 3.51 (s, 3H), 3.46-3.41 (m, 2H), 2.36 (s, 3H).

Example 232-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(quinazolin-6-yl)propanamide23

Compound 8i (90 mg, 204.6 μmol), quinazolin-6-amine 23a (32.67 mg,225.06 μmol, prepared by a known method disclosed in “Bioorganic &Medicinal Chemistry Letters, 2015, 25(4), 803-806”) andN,N-diisopropylethylamine (264.42 mg, 2.05 mmol) were added to 15 mL ofethyl acetate, followed by dropwise addition of a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 537.94 mg, 845.36 μmol). After completion of theaddition, the reaction solution was warmed up to 75° C., and stirred for2 hours. After cooling to room temperature, the reaction solution wasadded with 30 mL of water, followed by addition of 3M hydrochloride toadjust the pH to 5, and two phases were separated. The water phase wasextracted with ethyl acetate (30 mL×2). The organic phases werecombined, and washed with the saturated sodium chloride solution (35mL×2), dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography with elution system A toobtain the title compound 23 (50 mg, yield: 43.1%).

MS m/z (ESI): 567.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.59 (s, 1H), 9.22 (s, 1H),8.63 (s, 1H), 8.04 (q, 2H), 7.81 (d, 1H), 7.60 (d, 1H), 7.43 (s, 1H),7.37 (s, 1H), 7.31-7.27 (m, 4H), 7.22-7.20 (m, 1H), 6.32 (s, 1H),6.07-6.03 (m, 1H), 3.53 (s, 3H), 3.51-3.48 (m, 2H), 2.85-2.67 (m, 2H),0.98 (t, 3H).

Example 244-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide24

In accordance with the synthetic route of Example 23, the startingcompound 23a was replaced with 4-aminobenzamide (prepared by a knownmethod disclosed in “Chemical Communications (Cambridge, UnitedKingdom), 2017, 53(35), 4807-4810”), accordingly, the title compound 24(150 mg) was prepared.

MS m/z (ESI): 558.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.89-7.86 (m, 2H), 7.82-7.81 (m, 1H),7.77-7.70 (m, 2H), 7.58-7.55 (m, 1H), 7.34-7.29 (m, 7H), 7.25-7.23 (m,1H), 6.43 (s, 1H), 5.92-5.89 (m, 1H), 3.63-3.58 (m, 1H), 3.57 (s, 3H),3.47-3.41 (m, 2H), 1.12-1.09 (m, 3H).

Examples 25, 26(R)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide25(S)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzamide26

Compound 24 (150 mg, 268.81 μmol) was separated chirally (separationconditions: chiral preparative column CHIRALPAK IF 250*20 mm; mobilephase: A n-hexane:B ethanol=60:40, flow rate: 7.0 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 25 (50 mg) and compound 26 (50mg).

Compound 25:

MS m/z (ESI): 558.5 [M+1]

Chiral HPLC analysis: retention time 6.587 minutes, (chromatographiccolumn: Lux Amylose-2 (AY) 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol/n-hexane=20/80 (v/v)).

¹H NMR (400 MHz, MeOH-d₄) δ 7.89-7.86 (m, 2H), 7.82-7.81 (m, 1H),7.77-7.70 (m, 2H), 7.58-7.55 (m, 1H), 7.34-7.29 (m, 7H), 7.25-7.23 (m,1H), 6.43 (s, 1H), 5.92-5.89 (m, 1H), 3.63-3.58 (m, 1H), 3.57 (s, 3H),3.47-3.41 (m, 2H), 1.12-1.09 (m, 3H).

Compound 26:

MS m/z (ESI): 558.4 [M+1]

Chiral HPLC analysis: retention time 8.966 minutes, (chromatographiccolumn: Lux Amylose-2 (AY) 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol/n-hexane=20/80 (v/v)).

¹H NMR (400 MHz, CD₃OD) δ 7.89-7.86 (m, 2H), 7.82-7.81 (m, 1H),7.77-7.70 (m, 2H), 7.58-7.55 (m, 1H), 7.34-7.29 (m, 7H), 7.25-7.23 (m,1H), 6.43 (s, 1H), 5.92-5.89 (m, 1H), 3.63-3.58 (m, 1H), 3.57 (s, 3H),3.47-3.41 (m, 2H), 1.12-1.09 (m, 3H).

Example 272-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-indazol-6-yl)-3-phenylpropanamide27

In accordance with the synthetic route of Example 23, the startingcompound 23a was replaced with 6-aminoindazole (prepared by a knownmethod disclosed in “Tetrahedron Letters, 2010, 51(5), 786-789”),accordingly, the title compound 27 (45 mg) was prepared.

MS m/z (ESI): 555.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (s, 1H), 10.68 (s, 1H), 8.14 (s, 1H),7.99 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H) 7.60 (d, 1H), 7.45 (s, 1H),7.38 (s, 1H), 7.30-7.26 (m, 4H), 7.21-7.16 (m, 2H), 6.30 (s, 1H),6.07-6.03 (m, 1H), 3.53 (s, 3H), 3.50-3.47 (m, 2H), 2.85-2.67 (m, 2H),0.97 (t, 3H).

Example 282-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-cyano-1H-indole-6-yl)-3-phenylpropanamide28

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 6-amino-1H-indole-3-carbonitrile(prepared by a method disclosed in the patent application “US20160271105”), accordingly, the title compound 28 (30 mg) was prepared.

MS m/z (ESI): 565.0 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.03 (s, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.55(t, 2H), 7.41 (s, 1H), 7.31-7.15 (m, 7H), 6.42 (s, 1H), 5.96-5.93 (m,1H), 3.58 (s, 3H), 3.43-3.38 (m, 2H), 2.44 (s, 3H).

Example 29 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-3-fluorobenzoic acid 29

In accordance with the synthetic route of Example 4, the startingcompound 4c used in Step 2 was replaced with methyl4-amino-3-fluorobenzoate (prepared by a method disclosed in the patentapplication “WO 2012087519”), accordingly, the title compound 29 (20 mg)was prepared.

MS m/z (ESI): 563.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.15-8.11 (m, 1H), 7.85-7.80(d, 1H), 7.79-7.72 (m, 2H), 7.61-7.59 (dd, 1H), 7.38-7.37 (d, 2H),7.34-7.32 (d, 2H), 7.29-7.25 (m, 2H), 7.20-7.17 (m, 1H), 6.31 (s, 1H),6.23-6.19 (m, 1H), 3.57-3.45 (m, 5H), 2.36 (s, 3H).

Example 304-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 30

Step 1 1-(4-chloro-2-(2,5-dimethoxypyridin-4-yl)-3-fluorophenyl)ethanone30b

1-(2-Bromo-4-chloro-3-fluorophenyl)ethanone 30a (630 mg, 2.51 mmol,prepared by a method disclosed in the patent application“WO2013056034”), compound 1d (550.05 mg, 3.01 mmol),tetrakis(triphenylphosphine)palladium (868.46 mg, 0.75 mmol) and sodiumcarbonate (796.57 mg, 7.52 mmol) were added to a mixed solvent of 3 mLof 1,4-dioxane and 1 mL of water. After completion of the addition, thereaction solution was heated to 95° C. and stirred for 16 hours. Aftercooling to room temperature naturally, the reaction solution was addedwith 50 mL of water and extracted with ethyl acetate (50 mL×2). Theorganic phases were combined, washed with saturated sodium chloridesolution (50 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 30b (650 mg, yield: 83.7%).

MS m/z (ESI): 310.3 [M+1]

Step 2 4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxypyridin-2(1H)-one30c

Compound 30b (650 mg, 2.1 mmol) was dissolved in 20 mL of 1,4-dioxane,followed by addition of concentrated hydrochloric acid (20 mL, 240mmol). After completion of the addition, the reaction solution washeated to 110° C., and stirred for 16 hours. After cooling to roomtemperature, the reaction solution was concentrated under reducedpressure to remove the organic solvent. The resulting residue was addedwith 20 mL of water, neutralized with saturated sodium bicarbonatesolution, and extracted with ethyl acetate (30 mL×3). The organic phaseswere combined, washed with saturated sodium chloride solution (50 mL),dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography with elution system A toobtain the title compound 30c (418 mg, yield: 67.4%).

MS m/z (ESI): 296.1 [M+1]

Step 32-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoicacid 30d

Compound 30c (243 mg, 0.82 mmol) was dissolved in 50 mL oftetrahydrofuran, and then compound 4a (282.38 mg, 1.23 mmol), potassiumtert-butoxide (404.07 mg, 3.6 mmol) and magnesium tert-butoxide (280.29mg, 1.64 mmol) were added. The reaction solution was heated to 65° C.and stirred for 16 hours. After cooling to room temperature, thereaction solution was added with IMhydrochloric acid to adjust the pH to3, and extracted with ethtyl acetate (150 mL×2). The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem A to obtain the title compound 30d (200 mg, yield: 54.8%).

MS m/z (ESI): 444.4 [M+1]

Step 4 methyl4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 30e

Compound 30d (200 mg, 0.45 mmol), compound 4c (68.11 mg, 0.45 mmol) andN,N-diisopropylethylamine (58.24 mg, 0.45 mmol) were dissolved in 5 mLof ethyl acetate, under ice bath, followed by dropwise addition of asolution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 286.74 mg, 0.45 mmol) in an ice bath. Aftercompletion of the addition, the reaction solution was warmed up to 65°C., and stirred for 1 hour. After cooling to room temperature, thereaction solution was added with saturated sodium bicarbonate solutionto quench the reaction, and extracted with ethyl acetate (150 mL×2). Theorganic phases were combined, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography withelution system A to obtain the title compound 30e (120 mg, yield:46.2%).

MS m/z (ESI): 575.4 [M−1]

Step 54-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 30

Compound 30e (120 mg, 0.21 mmol) was dissolved in 8 mL of1,2-dichloroethane, and then trimethyltin hydroxide (564.08 mg, 3.12mmol) was added. The reaction solution was warmed up to 90° C., andstirred for 48 hours. After cooling to room temperature naturally, thereaction solution was filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by highpressure liquid chromatography (Waters 2767-SQ detecor2, elution system:acetonitrile, water) to obtain the title compound 30 (40 mg, yield:32.8%).

MS m/z (ESI): 563.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.75-7.67 (m, 4H), 7.45 (d, 1H),7.31-7.29 (m, 4H), 7.26-7.22 (m, 1H), 6.40 (s, 1H), 5.97-5.91 (m, 1H),3.63 (d, 3H), 3.61-3.40 (m, 2H), 2.45 (d, 3H).

Examples 31, 32(S)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 31(R)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 32

Compound 30 (35 mg, 0.06 mmol) was separated chirally (separationconditions: chiral preparative column CHIRALPAK ID, 5.0 cm I.D.*25 cm L,mobile phase: ethanol/dichloromethane/acetic acid=90/10/0.1 (V/V/V),flow rate: 60 mL/min). The corresponding fractions were collected andconcentrated under reduced pressure to obtain the title compound 31 (11mg) and compound 32 (11 mg).

Compound 31:

MS m/z (ESI): 563.2 [M+1]

Chiral HPLC analysis: retention time 8.000 minutes, chiral purity: 98%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guardcolumn), mobile phase: ethanol (with 0.1% trifluoroaceticacid)/n-hexane=50/50 (V/V), flow rate: 1.0 mL/min).

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.75-7.67 (m, 4H), 7.45 (d, 1H),7.31-7.29 (m, 4H), 7.26-7.22 (m, 1H), 6.40 (s, 1H), 5.97-5.91 (m, 1H),3.63 (d, 3H), 3.61-3.40 (m, 2H), 2.45 (d, 3H).

Compound 32:

MS m/z (ESI): 563.2 [M+1]

Chiral HPLC analysis: retention time 3.777 minutes, chiral purity: 100%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guardcolumn), mobile phase: ethanol (with 0.1% trifluoroaceticacid)/n-hexane=50/50 (V/V), flow rate: 1.0 mL/min)

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.75-7.67 (m, 4H), 7.45 (d, 1H),7.31-7.29 (m, 4H), 7.26-7.22 (m, 1H), 6.40 (s, 1H), 5.97-5.91 (m, 1H),3.63 (d, 3H), 3.61-3.40 (m, 2H), 2.45 (d, 3H).

Example 33 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-imidazo[4,5-b]pyridin-5-yl)-3-phenylpropanamide

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 1H-imidazo [4,5-b]pyridine-5-amine,accordingly, the title compound 33 (40 mg) was prepared.

MS m/z (ESI): 542.5 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 10.55 (s, 1H), 8.18 (s, 1H), 8.08 (s, 2H),7.71 (d, 1H), 7.52-7.50 (dd, 1H), 7.34 (d, 1H), 7.12 (m, 5H), 6.65 (s,1H), 6.26 (s, 1H), 3.69 (s, 3H), 3.68-3.64 (m, 1H), 3.34-3.29 (m, 1H),2.49 (s, 3H).

Example 34 methyl(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 34

Compound 5 (60 mg, 110.10 μmol) was dissolved in 5 mL ofdichloromethane, and then methanol (35.27 mg, 1.1 mmol),4-dimethylaminopyridine (20.34 mg, 165.14 μmol) and1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.54 mg,165.14 mol) were added. After stirring for 16 hours, the reactionsolution was added with 20 mL of saturated sodium bicarbonate solution,and extracted with dichloromethane (50 mL×2). The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 34 (35 mg, yield: 56.9%).

MS m/z (ESI): 559.2 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.97-7.96 (m, 1H), 7.95-7.94(m, 1H), 7.83-7.81 (d, 1H), 7.80-7.79 (m, 1H), 7.78-7.77 (m, 1H),7.62-7.59 (m, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.30-7.25 (m, 4H),7.21-7.17 (m, 1H), 6.31 (s, 1H), 6.05-6.01 (m, 1H), 3.83 (s, 3H), 3.53(s, 3H), 3.52-3.42 (m, 2H), 2.37 (s, 3H).

Example 354-(2-(4-(5-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid 35

In accordance with the synthetic route of Example 8, the startingcompound 8c was replaced with1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanone (prepared by a methoddisclosed in the patent application “WO2011100285”), accordingly, thetitle compound 35 (10 mg) was prepared.

MS m/z (ESI): 599.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.77 (s, 1H), 8.10-8.08 (m, 2H), 7.83-7.80 (m,3H), 7.60-7.58 (m, 1H), 7.43 (s, 1H), 7.36-7.26 (m, 5H), 6.70 (s, 1H),6.14 (br, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 3H), 3.33-3.28 (m, 1H).

Example 36 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-cyano-3-methoxyphenyl)-3-phenylpropanamide 36

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 4-amino-2-methoxybenzonitrile (preparedby a method disclosed in the patent application “WO 2013042782”),accordingly, the title compound 36 (40 mg) was prepared.

MS m/z (ESI): 556.5 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.89 (s, 1H), 7.73 (d, 1H), 7.54-7.51 (dd,1H), 7.48 (d, 1H), 7.41 (s, 1H), 7.29 (s, 4H), 7.21 (s, 1H), 7.09-7.06(dd, 2H), 6.59 (s, 1H), 6.00 (s, 1H), 3.90 (s, 3H), 3.69-3.75 (m, 1H),3.65 (s, 3H), 3.33-3.28 (m, 1H), 2.50 (s, 3H).

Example 37(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N-ethylbenzamide

In accordance with the synthetic route of Example 13, the startingmaterial methylamine was replaced with ethylamine, accordingly, thetitle compound 37 (40 mg) was prepared.

MS m/z (ESI): 572.1 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.61 (br, 1H), 7.73-7.64 (m, 5H), 7.51 (d,1H), 7.36-7.30 (m, 4H), 7.29-7.24 (m, 1H), 7.13 (s, 1H), 6.64 (s, 1H),6.11 (s, 1H), 5.99-5.96 (m, 1H), 3.76-3.73 (m, 1H), 3.64 (s, 3H),3.53-3.51 (m, 2H), 3.34-3.31 (m, 1H), 2.47 (s, 3H), 1.28 (t, 3H).

Example 38N-(1H-benzo[d]imidazol-5-yl)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide38

Compound 8i (80 mg, 181.86 μmol), 1H-benzo[d]imidazol-5-amine 38a (24.22mg, 181.86 μmol, prepared by a known method disclosed in “ChemicalCommunications (Cambridge, United Kingdom), 2011, 47(39), 10972-10974”)and N,N-diisopropylethylamine (70.51 mg, 545.59 μmol) were added to 10mL of tetrahydrofuran, followed by addition of a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 231.34 mg, 363.73 μmol). After completion of theaddition, the reaction solution was warmed up to 50° C., and stirred for1.5 hours. The reaction solution was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was addedwith 25 mL of saturated sodium bicarbonate solution, and extracted withethyl acetate (50 mL×2). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by thesilica gel column with elution system A to obtain the title compound 38(75 mg, yield: 74.3%).

MS m/z (ESI): 555.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.05 (s, 1H), 9.14 (s, 1H),8.27 (s, 1H), 7.79-7.77 (d, 1H), 7.72-7.69 (d, 1H), 7.59-7.52 (m, 2H),7.41 (s, 1H), 7.34 (s, 1H), 7.30-7.24 (m, 4H), 7.19-7.17 (m, 1H), 6.30(s, 1H), 6.03-5.99 (m, 1H), 3.52-3.50 (m, 4H), 3.48-3.44 (m, 1H),2.85-2.75 (m, 2H), 1.25-1.18 (m, 3H).

Example 394-(2-(4-(5-chloro-2-(2-cyclopropylacetyl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid

In accordance with the synthetic route of Example 8, the startingcompound 8b was replaced with cyclopropylacetyl chloride (prepared by amethod disclosed in the patent application “WO 2015110435”), thestarting material cuprous chloride was replaced with cuprous iodide,accordingly, the title compound 39 (30 mg) was prepared.

MS m/z (ESI): 585.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.93 (br, 1H), 8.10-8.08 (m, 2H), 7.85-7.83(m, 2H), 7.69-7.67 (m, 1H), 7.51-7.48 (m, 1H), 7.35-7.26 (m, 6H), 6.63(s, 1H), 6.22 (br, 1H), 3.69-3.64 (m, 4H), 3.62-3.29 (m, 1H), 2.74-2.72(m, 2H), 1.07-1.05 (m, 1H), 0.61-0.59 (m, 2H), 0.15-0.14 (m, 2H).

Example 402-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(quinazolin-6-yl)propanamide40

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with compound 23a, accordingly, the titlecompound 40 (80 mg) was prepared.

MS m/z (ESI): 553.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.59 (s, 1H), 9.22 (s, 1H),8.63 (s, 1H), 8.07-8.01 (m, 2H), 7.83 (d, 1H), 7.61 (dd, 1H), 7.46 (s,1H), 7.38 (s, 1H), 7.32-7.26 (m, 4H), 7.22-7.18 (m, 1H), 6.33 (s, 1H),6.10-6.06 (m, 1H), 3.56 (s, 3H), 3.52 (d, 2H), 2.40 (s, 3H).

Example 414-(2-(4-(5-chloro-2-(cyclopropanecarbonyl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 41

In accordance with the synthetic route of Example 8, the startingcompound 8b was replaced with cyclopropanoyl chloride (prepared by amethod disclosed in the patent application “WO 2015143380”),accordingly, the title compound 41 (60 mg) was prepared.

MS m/z (ESI): 571.2 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H), 7.92 (d, 2H), 7.75-7.72 (m,3H), 7.61 (dd, 1H), 7.38 (d, 2H), 7.31-7.24 (m, 4H), 7.20-7.17 (m, 1H),6.34 (s, 1H), 6.05-6.01 (m, 1H), 3.57-3.49 (m, 2H), 3.52 (s, 3H),2.18-2.11 (m, 1H), 0.85-0.75 (m, 4H).

Example 42 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-indazol-6-yl)-3-phenylpropanamide 42

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 6-aminocarbazole (prepared by a knownmethod disclosed in “Tetrahedron Letters, 2010, 51(5), 786-789”),accordingly, the title compound 42 (83 mg) was prepared.

MS m/z (ESI): 541.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (s, 1H), 10.67 (s, 1H), 8.13 (s, 1H),7.99 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.48 (s, 1H),7.38 (s, 1H), 7.31-7.25 (m, 4H), 7.21-7.16 (m, 2H), 6.31 (s, 1H),6.08-6.04 (m, 1H), 3.56 (s, 3H), 3.47 (d, 2H), 2.38 (s, 3H).

Example 43(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N-cyclopropylbenzamide 43

In accordance with the synthetic route of Example 13, the startingmaterial methylamine is replaced with cyclopropylamine, accordingly, thetitle compound 43 (40 mg) was prepared.

MS m/z (ESI): 584.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.37 (d, 1H), 7.84-7.80 (m,3H), 7.70 (d, 2H), 7.61 (dd, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.31-7.26(m, 4H), 7.22-7.18 (m, 1H), 6.31 (s, 1H), 6.04-6.00 (m, 1H), 3.55 (s,3H), 3.50-3.42 (m, 2H), 2.85-2.80 (m, 1H), 2.38 (s, 3H), 0.71-0.54 (m,4H).

Example 444-(2-(4-(5-chloro-2-isobutyrylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoicacid 44

In accordance with the synthetic route of Example 8, the startingcompound 8b was replaced with isobutyryl chloride (prepared by a knownmethod disclosed in “Organic Letters, 2017, 19(7), 1768-1771”),accordingly, the title compound 44 (200 mg) was prepared.

MS m/z (ESI): 573.5 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 8.10 (d, 2H), 7.86 (d, 2H), 7.72(d, 1H), 7.52-7.29 (m, 8H), 6.59 (s, 1H), 6.28 (s, 1H), 3.67-3.62 (m,4H), 3.33-3.23 (m, 2H), 1.15-1.12 (m, 6H).

Example 452-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide45

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 6-aminoquinoxaline (prepared by a methoddisclosed in the patent application “WO2013006792”), accordingly, thetitle compound 45 (45 mg) was prepared.

MS m/z (ESI): 553.0 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.85-8.83 (d, 1H), 8.83-8.80 (d, 1H),8.61-8.57 (m, 1H), 8.08-8.04 (d, 1H), 8.02-7.94 (dd, 1H), 7.85-7.83 (d,1H), 7.58-7.55 (dd, 1H), 7.39 (s, 1H), 7.33-7.27 (m, 5H), 7.23-7.20 (m,1H), 6.43 (s, 1H), 6.00-5.95 (m, 1H), 3.65-3.60 (m, 1H), 3.59 (s, 3H),3.50-3.45 (m, 1H), 2.46 (s, 3H).

Example 46 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(isoquinolin-6-yl)-3-phenylpropanamide 46

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 6-aminoisoquinoline (prepared by a methoddisclosed in the patent application “WO 2010146881”), accordingly, thetitle compound 46 (88 mg) was prepared.

MS m/z (ESI): 552.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.20 (s, 1H), 8.44-8.43 (m,2H), 8.10 (d, 1H), 7.83 (d, 1H), 7.77-7.73 (m, 2H), 7.61 (d, 1H), 7.45(s, 1H), 7.38 (s, 1H), 7.32-7.26 (m, 4H), 7.21-7.18 (m, 1H), 6.32 (s,1H), 6.11-6.06 (m, 1H), 3.56 (s, 3H), 3.51 (d, 2H), 2.39 (s, 3H).

Example 47 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1H-benzo[d]imidazol-5-yl)-3-phenylpropanamide 47

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with compound 38a, accordingly, the titlecompound 47 (10 mg) was prepared.

MS m/z (ESI): 541.2 [M+1]

¹H NMR (400 MHz, MeOH-d₄) δ 8.18 (s, 1H), 8.03 (s, 1H), 7.84-7.82 (d,1H), 7.56-7.50 (d, 2H), 7.43 (s, 1H), 7.30-7.22 (m, 7H), 6.43 (s, 1H),5.89-5.85 (m, 1H), 3.65-3.60 (m, 1H), 3.59 (s, 3H), 3.50-3.45 (m, 1H),2.46 (s, 3H).

Example 482-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanamide48

Compound 4b (43 mg, 100.97 μmol),2-(trifluoromethyl)-1H-benzo[d]imidazole-5-amine 48a (20.31 mg, 100.97μmol, prepared by a known method disclosed in “International Journal ofPharmTech Research, 2009, 1(2), 277-281”) and N,N-diisopropylethylamine(39.15 mg, 302.92 μmol) were added to 15 mL of tetrahydrofuran, followedby addition of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (64.22mg, 201.94 μmol). After completion of the addition, the reactionsolution was warmed up to 60° C., and stirred for 1 hour. The reactionsolution was cooled to room temperature, and concentrated under reducedpressure. The resulting residue was added with 15 mL of saturated sodiumbicarbonate solution, and extracted with ethyl acetate (50 mL×2). Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel column with elution systemA to obtain the title compound 48 (50 mg).

MS m/z (ESI): 609.2 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 13.93-13.83 (d, 1H), 10.74-10.65 (d, 1H),8.25-8.15 (m, 1H), 7.84-7.82 (d, 1H), 7.78-7.74 (d, 1H), 7.62-7.60 (dd,1H), 7.50-7.45 (m, 1H), 7.44-7.36 (m, 2H), 7.35-7.25 (m, 4H), 7.22-7.15(m, 1H), 6.50 (s, 1H), 6.10-6.00 (m, 1H), 3.55 (s, 3H), 3.51-3.48 (m,2H), 2.38 (s, 3H).

Example 49 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-methyl-1H-benzo[d]imidazol-5-yl)-3-phenylpropanamide 49

In accordance with the synthetic route of Example 48, the startingcompound 48a was replaced with 2-methyl-1H-benzo[d]imidazole-5-amine(prepared by a method disclosed in the patent application“WO2012044090”), accordingly, the title compound 49 (40 mg) wasprepared.

MS m/z (ESI): 555.2 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.86 (s, 1H), 7.88-7.81 (d,1H), 7.61-7.59 (dd, 1H), 7.47 (s, 1H), 7.45-7.43 (d, 1H), 7.37 (s, 1H),7.31-7.24 (m, 5H), 7.21-7.17 (m, 1H), 6.30 (s, 1H), 6.05-6.01 (m, 1H),3.55 (s, 3H), 3.51-3.48 (m, 2H), 2.50 (s, 3H), 2.38 (s, 3H).

Example 50(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-N,N-dimethylbenzamide 50

In accordance with the synthetic route of Example 13, the startingmaterial methylamine was replaced with dimethylamine, accordingly, thetitle compound 50 (40 mg) was prepared.

MS m/z (ESI): 572.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.84 (d, 1H), 7.82 (d, 2H),7.70-7.68 (m, 1H), 7.44-7.40 (m, 4H), 7.31-7.28 (m, 4H), 7.21-7.18 (m,1H), 6.31 (s, 1H), 6.04-6.00 (m, 1H), 3.55 (s, 3H), 3.52-3.47 (m, 2H),2.96 (s, 6H), 2.38 (s, 3H).

Example 51 5-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)-2-picolinamide 51

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 5-amino-2-pyridinecarboxamide (preparedby a method disclosed in the patent application “WO2013146963”),accordingly, the title compound 51 (70 mg) was prepared.

MS m/z (ESI): 545.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.83-8.82 (d, 1H), 8.23-8.20 (dd, 1H),8.08-8.06 (d, 1H), 7.85-7.83 (d, 1H), 7.57-7.54 (dd, 1H), 7.32-7.29 (m,1H), 7.28-7.25 (m, 5H), 7.23-7.20 (m, 1H), 6.41 (s, 1H), 5.89-5.85 (m,1H), 3.65-3.60 (m, 1H), 3.59 (s, 3H), 3.50-3.45 (m, 1H), 2.46 (s, 3H).

Example 522-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(1H-pyrrolo[3,2-b]pyridin-6-yl)propanamide52

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 1H-pyrrolo[3,2-b]pyridine-6-amine(Accela), accordingly, the title compound 52 (23 mg) was prepared.

MS m/z (ESI): 541.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.69 (s, 1H), 8.08 (d, 1H),7.86 (d, 1H), 7.58-7.55 (m, 1H), 7.32-7.18 (m, 7H), 6.82 (d, 1H), 6.45(s, 1H), 5.76-5.73 (m, 1H), 3.63-3.61 (m, 1H), 3.51 (s, 3H), 3.50-3.48(m, 1H), 2.48 (s, 3H).

Example 53 methyl3-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzylcarbamate53

Step 1

tert-butyl3-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzylcarbamate53b

Compound 4b (90 mg, 211.34 μmol), tert-butyl 3-aminobenzylcarbamate 53a(51.68 mg, 232.47 μmol, prepared by a known method disclosed in“Chemical Communications (Cambridge, United Kingdom), 2014, 50 (97),15305-15308”) and N,N-diisopropylethylamine (273.14 mg, 2.11 mmol) weredissolved in 15 mL of ethyl acetate followed by addition of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide(268.97 mg, 845.36 mol). After completion of the addition, the reactionsolution was warmed up to 75° C., and stirred for 2 hours. After coolingto room temperature, the reaction solution was added with 30 mL ofwater, followed by addition of 3M hydrochloric acid to adjust the pH to5, and the two phases were separated. The water phase was extracted withethyl acetate (30 mL×2), and the organic phases were combined, washedwith saturated sodium chloride solution (35 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn with elution system A to obtain the title compound 53b (105 mg,yield: 78.85%).

MS m/z (ESI): 630.1 [M+1]

Step 2 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(aminomethyl) phenyl)-3-phenylpropanamide 53c

Compound 53b (105 mg, 166.63 μmol) was dissolved in 7 mL ofdichloromethane, and then trifluoroacetic acid (1 mL) was addeddropwise. The reaction solution was stirred for 1 hour, and thenconcentrated under reduced pressure to obtain the crude title compound53c (80 mg), which was directly used in the next reaction step withoutpurification.

MS m/z (ESI): 530.1 [M+1]

Step 3 methyl 3-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzylcarbamate 53

The crude compound 53c (80 mg, 105.94 μmol) was dissolved in 10 mL ofdichloromethane, and then triethylamine (61.096 mg, 603.76 μmol) wasadded dropwise, followed by dropwise addition of methyl chloroformate(21.40 mg, 226.41 μmol) in an ice bath. After stirring for 2 hours atroom temperature, the reaction solution was added with 25 ml ofdichloromethane, washed with 0.5 M hydrochloric acid (15 mL), saturatedsodium bicarbonate solution (15 mL) and saturated brine (15 mL)successively, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by high pressure liquid chromatography (Waters2767-SQ detecor2, elution system: acetonitrile, water) to obtain thetitle compound 53 (35 mg, 39.4%).

MS m/z (ESI): 588.3 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 7.66 (d, 1H), 7.47 (dd, 1H),7.43-7.41 (m, 2H), 7.28-7.20 (m, 7H), 7.12 (s, 1H), 7.04 (d, 1H), 6.55(s, 1H), 6.00-5.91 (m, 1H), 5.08 (s, 1H), 4.31 (d, 2H), 3.72-3.65 (m,1H), 3.68 (s, 3H), 3.60 (s, 3H), 3.28-3.23 (m, 1H), 2.43 (s, 3H).

Example 542-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-cyano-1H-indol-6-yl)-3-phenylpropanamide54

In accordance with the synthetic route of Example 38, the startingcompound 38a was replaced with 6-amino-1H-indole-2-carbonitrile(prepared by a method disclosed in the patent application“US20160271105”), accordingly, the title compound 54 (30 mg) wasprepared.

MS m/z (ESI): 579.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.78-7.79 (d, 1H), 7.59-7.57 (d,1H), 7.56-7.53 (dd, 1H), 7.38 (s, 1H), 7.33-7.25 (m, 5H), 7.25-7.18 (m,1H), 7.16-7.15 (d, 1H), 7.14-7.12 (dd, 1H), 6.42 (s, 1H), 5.95-5.90 (m,1H), 3.60-3.56 (m, 1H), 3.54 (s, 3H), 3.45-3.35 (m, 1H), 3.00-2.95 (m,2H), 1.10-1.00 (m, 3H).

Example 55 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-phenylpropanamide 55

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 4-amino-2-(trifluoromethyl)benzonitrile(prepared by a known method disclosed in “Medicinal Chemistry Research,2016, 25(4), 539-552”), accordingly, the title compound 55 (40 mg) wasprepared.

MS m/z (ESI): 594.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 7.75-7.72 (m, 2H), 7.55-7.51(m, 2H) 7.29-7.26 (m, 5H), 7.24-7.16 (m, 2H), 6.55 (s, 1H), 5.98 (s,1H), 3.71-3.67 (m, 1H), 3.65 (s, 3H), 3.33-3.27 (m, 1H), 2.51 (m, 3H).

Example 56 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(methylsulfonyl)phenyl)-3-phenylpropanamide 56

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 4-(methylsulfonyl)aniline (prepared by amethod disclosed in the patent application “WO2014100833”), accordingly,the title compound 56 (110 mg) was prepared.

MS m/z (ESI): 579.0 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 7.91-7.86 (m, 4H), 7.83 (d,1H), 7.61 (dd, 1H), 7.39 (d, 2H), 7.30-7.25 (m, 4H), 7.21-7.18 (m, 1H),6.32 (s, 1H), 6.03-5.99 (m, 1H), 3.53 (s, 3H), 3.50-3.45 (m, 2H), 3.18(s, 3H), 2.38 (s, 3H).

Example 572-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1,6-naphthyridin-3-yl)-3-phenylpropanamide57

In accordance with the synthetic route of Example 48, the startingcompound 48a was replaced with 1,6-naphthyridin-3-amine (prepared by amethod disclosed in the patent application “WO2007048070”), accordingly,the title compound 57 (40 mg) was prepared.

MS m/z (ESI): 553.2 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.40 (s, 1H), 9.14 (s, 1H),8.95 (s, 1H), 8.67-8.65 (d, 1H), 7.87-7.82 (m, 2H), 7.62-7.60 (d, 1H),7.48 (s, 1H), 7.38 (s, 1H), 7.30-7.26 (m, 4H), 7.21-7.20 (m, 1H), 6.36(s, 1H), 6.05-6.03 (m, 1H), 3.64-3.58 (m, 4H), 3.30-3.22 (m, 1H), 2.40(s, 3H).

Example 582-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenyl-N-(4-sulfamoylphenyl)propanamide58

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 4-(aminosulfonyl)aniline (prepared by aknown method disclosed in “Journal of Organic Chemistry, 2014, 79 (19),9433-9439”), accordingly, the title compound 58 (40 mg) was prepared.

MS m/z (ESI): 580.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.85-7.82 (m, 3H), 7.76-7.74 (m, 2H),7.56-7.54 (dd, 1H), 7.33-7.32 (m, 2H), 7.28-7.25 (m, 4H), 7.22-7.19 (m,1H), 6.41 (s, 1H), 5.89-5.85 (m, 1H), 3.65-3.60 (m, 1H), 3.59 (s, 3H),3.50-3.45 (m, 1H), 2.46 (s, 3H).

Example 59 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-cyano-2-fluorophenyl)-3-phenylpropanamide 59

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 4-amino-3-fluorobenzonitrile (prepared bya known method disclosed in “Journal of Medicinal Chemistry, 2005, 48(18), 5823-5836”), accordingly, the title compound 59 (20 mg) wasprepared.

MS m/z (ESI): 544.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.83 (s, 1H), 8.53 (t, 1H), 7.72 (d, 1H),7.53-7.50 (dd, 1H), 7.47 (d, 2H), 7.42-7.29 (dd, 1H), 7.37-7.32 (m, 4H),7.30-7.26 (m, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 5.86 (s, 1H), 3.82-3.74(m, 1H), 3.61 (s, 3H), 3.37-3.32 (m, 1H), 2.49 (m, 3H).

Example 602-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-phenylpropanamide 60

In accordance with the synthetic route of Example 18, the startingcompound 18a was replaced with 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one(prepared by a method disclosed in the patent application“US20100216783”), accordingly, the title compound 60 (50 mg) wasprepared.

MS m/z (ESI): 569.8 [M−1]

¹H NMR (400 MHz, CD₃OD) δ 10.10 (s, 1H), 7.85-7.83 (d, 1H), 7.58-7.55(dd, 1H), 7.39 (s, 1H), 7.38-7.36 (m, 2H), 7.29-7.25 (m, 4H), 7.23-7.20(m, 1H), 7.00-6.99 (dd, 1H), 6.91-6.81 (d, 1H), 6.43 (s, 1H), 5.89-5.85(m, 1H), 4.54 (s, 2H), 3.65-3.60 (m, 1H), 3.59 (s, 3H), 3.50-3.45 (m,1H), 2.46 (s, 3H).

Examples 61,62 (S)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate61 (R)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate62

In accordance with the synthetic route of Examples 14, 15, the startingcompound 14b was replaced with4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (prepared by a methoddisclosed in the patent application “CN103450146”). After chiralsperation (separation conditions: chromatographic column: SuperchiralS-AD (Chiralway), 2 cm ID*25 cm Length, 5 m; mobile phase: carbondioxide:isopropanol=60:40, flow rate: 50 g/min), the correspondingfractions were collected and concentrated under reduced pressure toobtain the title compound 61 (600 mg) and compound 62 (600 mg).

Compound 61

MS m/z (ESI): 657.5 [M+1]

Chiral HPLC analysis: retention time 7.283 minutes, chiral purity: 99.8%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guardcolumn); mobile phase: ethanol/methanol=50/50 (V/V), flow rate: 1.0mL/min).

¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 7.98-7.97 (m, 1H), 7.96-7.95(m, 1H), 7.83-7.79 (m, 3H), 7.62-7.59 (dd, 1H), 7.41 (s, 1H), 7.37 (s,1H), 7.30-7.26 (m, 4H), 7.20-7.17 (m, 1H), 6.30 (s, 1H), 6.04-5.95 (m,1H), 5.20 (s, 2H), 3.51 (s, 3H), 3.49-3.42 (m, 2H), 2.37 (s, 3H), 2.22(s, 3H).

Compound 62

MS m/z (ESI): 657.2 [M+1]

Chiral HPLC analysis: retention time 5.342 minutes, chiral purity: 99.8%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guardcolumn); mobile phase: ethanol/methanol=50/50 (V/V), flow rate: 1.0mL/min).

¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 7.98 (d, 2H), 7.84-7.80 (m,3H), 7.63-7.60 (m, 1H), 7.40 (d, 2H), 7.30-7.26 (m, 4H), 7.22-7.18 (m,1H), 6.31 (s, 1H), 6.04-6.01 (m, 1H), 5.20 (s, 2H), 3.54 (s, 3H),3.51-3.43 (m, 2H), 2.38 (s, 3H), 2.22 (s, 3H).

Example 634-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)benzoicacid 63

In accordance with the synthetic route of Example 4, the startingcompound 4a was replaced with 2-bromo-3-(4-fluorophenyl)propionic acid(prepared by a method disclosed in the patent application “U.S. Pat. No.5,981,529A”), accordingly, the title compound 63 (64 mg) was prepared.

MS m/z (ESI): 563.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.90 (d, 2H), 7.84 (d, 1H),7.71 (d, 2H), 7.61 (dd, 1H), 7.39 (s, 2H), 7.33-7.29 (m, 2H), 7.10 (t,2H), 6.30 (s, 1H), 6.03-5.99 (m, 1H), 3.55 (s, 3H), 3.50-3.41 (m, 2H),2.40 (s, 3H).

Example 64 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-bromophenyl)propanamido)benzoic acid 64

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-bromo-2-(bromomethyl)benzene (preparedby a known method disclosed in “Bioorganic & Medicinal ChemistryLetters, 2014, 24(21), 5127-5133”), accordingly, the title compound 64(8 mg) was prepared.

MS m/z (ESI): 625.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.02-7.98 (m, 2H), 7.87 (d, 1H), 7.74-7.72 (m,2H), 7.62-7.57 (m, 2H), 7.34 (d, 1H), 7.29-7.26 (m, 3H), 7.19-7.15 (m,1H), 6.43 (s, 1H), 5.93-5.89 (m, 1H), 3.79-3.74 (m, 1H), 3.63-3.60 (m,1H), 3.58 (s, 3H), 2.51 (s, 3H).

Example 654-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2,4-difluorophenyl)propanamido)benzoicacid 65

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-(bromomethyl)-2,4-difluorobenzene(prepared by a method disclosed in the patent application“WO2012177638”), accordingly, the title compound 65 (8 mg) was prepared.

MS m/z (ESI): 581.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.02-7.99 (m, 2H), 7.87 (d, 1H), 7.74-7.72 (m,2H), 7.58 (dd, 1H), 7.36-7.28 (m, 3H), 6.98-6.90 (m, 2H), 6.41 (s, 1H),5.91 (br, 1H), 3.63-3.59 (m, 4H), 3.52-3.46 (m, 1H), 2.52 (s, 3H).

Example 664-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(o-tolyl)propanamido)benzoic acid 66

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-(bromomethyl)-2-methylbenzene (preparedby a known method disclosed in “Journal of Organic Chemistry, 2014,79(1), 223-229”), accordingly, the title compound 66 (60 mg) wasprepared.

MS m/z (ESI): 559.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.09 (d, 2H), 7.86 (d, 2H), 7.72(d, 1H), 7.52-7.50 (m, 2H), 7.30 (s, 1H), 7.19-7.13 (m, 4H), 6.63 (s,1H), 6.30 (s, 1H), 3.69-3.62 (m, 4H), 3.28-3.24 (m, 1H), 2.52-2.46 (m,6H).

Example 674-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(m-tolyl)propanamido)benzoic acid 67

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-(bromomethyl)-3-methylbenzene (preparedby a known method disclosed in “Chemical Communications (Cambridge,United Kingdom), 2014, 50 (28), 3692-3694), accordingly, the titlecompound 67 (80 mg) was prepared.

MS m/z (ESI): 559.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H), 8.10 (d, 2H), 7.84-7.71 (m, 3H),7.52-7.50 (m, 1H), 7.31 (s, 2H), 7.21-7.07 (m, 4H), 6.65 (s, 1H), 6.18(s, 1H), 3.67-3.59 (m, 4H), 3.27-3.22 (m, 1H), 2.66 (s, 3H), 2.33 (s,3H).

Example 684-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-fluorophenyl)propanamido)benzoicacid 68

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-(bromomethyl)-2-fluorobenzene (preparedby a known method disclosed in “Tetrahedron Letters, 2000, 41(27),5161-5164”), accordingly, the title compound 68 (55 mg) was prepared.

MS m/z (ESI): 563.2 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 7.90-7.89 (m, 1H), 7.90-7.89(m, 1H), 7.84-7.82 (d, 1H), 7.73-7.72 (m, 1H), 7.71-7.70 (m, 1H),7.62-7.60 (dd, 1H), 7.40-7.38 (d, 2H), 7.33-7.29 (m, 1H), 7.28-7.24 (m,1H), 7.16-7.12 (m, 1H), 7.10-7.08 (m, 1H), 6.33 (s, 1H), 6.04-5.95 (m,1H), 3.51 (s, 3H), 3.49-3.42 (m, 2H), 2.39 (s, 3H).

Example 69 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-chlorophenyl)propanamido)benzoic acid 69

In accordance with the synthetic route of Example 4, the startingcompound 4a was replaced with 2-bromo-3-(4-chlorophenyl)propionic acid(prepared by a method disclosed in the patent application“WO2012118216”), accordingly, the title compound 69 (15 mg) wasprepared.

MS m/z (ESI): 579.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.95-7.94 (m, 1H), 7.93-7.92(m, 1H), 7.85-7.83 (d, 1H), 7.78-7.77 (m, 1H), 7.76-7.75 (m, 1H),7.63-7.61 (m, 1H), 7.43-7.42 (m, 1H), 7.41-7.40 (m, 1H), 7.36-7.34 (m,2H), 7.31-7.29 (m, 2H), 6.33 (s, 1H), 6.04-5.95 (m, 1H), 3.51 (s, 3H),3.49-3.42 (m, 2H), 2.39 (s, 3H).

Example 70 4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-chlorophenyl)propanamido)benzoic acid 70

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-(bromomethyl)-2-chlorobenzene (preparedby a known method disclosed in “Tetrahedron Letters, 2016, 57(2),168-171”), accordingly, the title compound 70 (25 mg) was prepared.

MS m/z (ESI): 579.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.81 (s, 1H), 8.10 (d, 2H), 7.83 (d, 2H), 7.72(d, 1H), 7.51 (d, 1H), 7.35-7.30 (m, 1H), 7.30-7.29 (m, 1H), 7.29-7.28(m, 2H), 7.27-7.23 (m, 2H), 6.62 (s, 1H), 6.30 (s, 1H), 3.77-3.71 (m,1H), 3.69 (s, 3H), 3.52-3.49 (m, 1H), 2.51 (s, 3H).

Example 714-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-methoxyphenyl)propanamido)benzoicacid 71

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 1-(bromomethyl)-3-methoxybenzene (preparedby a method disclosed in the patent application “WO2014135095”),accordingly, the title compound 71 (48 mg) was prepared.

MS m/z (ESI): 575.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.91 (d, 2H), 7.82 (d, 1H),7.73 (d, 2H), 7.61 (dd, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.18 (t, 1H),6.89-6.85 (m, 2H), 6.76 (dd, 1H), 6.32 (s, 1H), 6.06-6.02 (m, 1H), 3.70(s, 3H), 3.54 (s, 3H), 3.47-3.44 (m, 2H), 2.37 (s, 3H).

Example 72(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-methoxyphenyl)propanamido)benzoicacid 72

Compound 71 (48 mg, 83.48 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IF, 20*250 mm, 5 μm;mobile phase: ethanol (containing 0.01% trifluoroacetic acid)=100, flowrate: 7 mL/min). The corresponding fractions were collected andconcentrated under reduced pressure to obtain the title compound 72 (18mg).

MS m/z (ESI): 575.4 [M+1]

Chiral HPLC analysis: retention time 8.546 min, chiral purity: 98%(chromatographic column: Lux Amylose-1 (AD) 4.6*150 mm 5 μm (with aguard column); mobile phase: ethanol (containing 0.1% trifluoroaceticacid)/n-hexane=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 10.88 (s, 1H), 7.92 (d, 2H),7.82 (d, 1H), 7.76 (d, 2H), 7.61 (dd, 1H), 7.42 (s, 1H), 7.38 (s, 1H),7.18 (t, 1H), 6.90-6.86 (m, 2H), 6.76 (dd, 1H), 6.32 (s, 1H), 6.05-6.01(m, 1H), 3.70 (s, 3H), 3.54 (s, 3H), 3.48-3.42 (m, 2H), 2.37 (s, 3H).

Example 73 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-chlorophenyl)propanamido)benzoate 73

In accordance with the synthetic route of compound 7f, the startingcompound 7c was replaced with 1-(bromomethyl)-2-chlorobenzene (preparedby a known method disclosed in “Tetrahedron Letters, 2016, 57(2),168-171”), accordingly, the title compound 73 (70 mg) was prepared.

MS m/z (ESI): 593.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 10.17 (s, 1H), 8.00 (d, 2H), 7.69-7.62 (m,3H), 7.49 (d, 1H), 7.31 (d, 2H), 7.25-7.16 (m, 4H), 6.47 (s, 1H), 6.23(s, 1H), 3.93 (s, 3H), 3.76-3.74 (m, 1H), 3.65 (s, 3H), 3.55-3.52 (m,1H), 2.48 (s, 3H).

Example 744-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(p-tolyl)propanamido)benzoicacid 74

Step 1 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(p-tolyl)propanoate74b

Compound 7b (100 mg, 0.26 mmol) and 1-(bromomethyl)-4-methylbenzene 74a(94.45 mg, 0.51 mmol, prepared by a known method disclosed in“Tetrahedron Letters, 2016, 57(22), 2430-2433”) were dissolved in 6 mLof tetrahydrofuran. The reaction solution was cooled to −78° C.,dropwise added with lithium bis(trimethylsilyl)amide solution (1.02 mL,1.02 mmol), and stirred for 2 hours. The reaction solution was addedwith 15 mL of saturated ammonium chloride solution to quench thereaction, and then warmed up to room temperature, and extracted withethyl acetate (50 mL×2). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by silicagel column chromatography with elution system B to obtain the titlecompound 74b (120 mg, yield: 94.8%).

MS m/z (ESI): 496.2 [M+1]

Step 22-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(p-tolyl)propanoicacid 74c

Compound 74b (100 mg, 0.20 mmol) was dissolved in 4 mL ofdichloromethane, and then trifluoroacetic acid (0.5 mL) was addeddropwise. The reaction solution was stirred for 5 hours, and thenconcentrated under reduced pressure to obtain the crude title compound74c (80 mg), which was directly used in the next reaction step withoutpurification.

MS m/z (ESI): 440.0 [M+1]

Step 34-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(p-tolyl)propanamido)benzoic acid 74

The crude compound 74c (80 mg, 0.18 mmol) and compound 8j (68.52 mg,0.27 mmol) were dissolved in 10 mL of ethyl acetate, and thenN,N-diisopropylethylamine (112.43 mg, 0.87 mmol) and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 415.18 mg, 0.65 mmol) were added dropwise. Aftercompletion of the addition, the reaction solution was warmed up to 60°C., and stirred for 2 hours. The reaction solution was added with 15 mLof water, and extracted with ethyl acetate (15 mL×2). The organic phaseswere combined, washed with saturated sodium chloride solution (15 mL×2),dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by high performance liquid chromatography (Waters 2767-SQdetecor2, elution system: acetonitrile, water) to obtain the titlecompound 74 (40 mg, yield: 39.4%).

MS m/z (ESI): 559.1 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.92 (s, 1H), 8.10 (d, 2H), 7.84 (d, 2H), 7.71(d, 1H), 7.56-7.50 (m, 2H), 7.30 (s, 1H), 7.23-7.11 (m, 4H), 6.64 (s,1H), 6.20 (s, 1H), 3.67-3.59 (m, 4H), 3.27-3.22 (m, 1H), 2.49 (s, 3H),2.31 (s, 3H).

Example 754-(3-(4-acetamidophenyl)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propanamido)benzoicacid 75

In accordance with the synthetic route of Example 16, the startingcompound propionyl chloride was replaced with acetyl chloride,accordingly, the title compound 75 (10 mg) was prepared.

MS m/z (ESI): 602.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.89 (s, 1H), 7.92 (d, 2H),7.83 (d, 1H), 7.76 (d, 2H), 7.61 (dd, 1H), 7.46 (d, 2H), 7.41 (d, 2H),7.18 (d, 2H), 6.30 (s, 1H), 6.00-5.96 (m, 1H), 3.55 (s, 3H), 3.42-3.39(m, 2H), 2.39 (s, 3H), 2.00 (s, 3H).

Example 764-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2,6-dichlorophenyl)propanamido)benzoicacid 76

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 2-(bromomethyl)-1,3-dichlorobenzene(prepared by a known method disclosed in “Organic Letters, 2017, 19(7),1634-1637”), accordingly, the title compound 76 (20 mg) was prepared.

MS m/z (ESI): 613.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.00 (dd, 2H), 8.86-7.88 (m, 1H), 7.74-7.70(m, 2H), 7.52-7.50 (m, 1H), 7.42-7.40 (m, 2H), 7.34 (d, 2H), 7.25 (t,1H), 6.87 (s, 1H), 6.42 (s, 1H), 3.92-3.82 (m, 1H), 3.64-3.52 (m, 4H),2.51 (d, 3H).

Example 774-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(5-fluoro-2-methylphenyl)propanamido)benzoicacid 77

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 2-(bromomethyl)-4-fluoro-1-methylbenzene(Adamas), accordingly, the title compound 77 (30 mg) was prepared.

MS m/z (ESI): 577.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 8.11 (d, 2H), 7.87 (d, 2H), 7.73(d, 1H), 7.53-7.50 (m, 2H), 7.31 (s, 1H), 7.15-7.14 (m, 1H), 6.87-6.66(m, 2H), 6.66 (s, 1H), 6.28 (s, 1H), 3.70-3.59 (m, 4H), 3.23-3.19 (m,1H), 2.53 (s, 3H), 2.46 (s, 3H).

Example 784-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-methoxyphenyl)propanamido)benzoicacid 78

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 1-(bromomethyl)-2-methoxybenzene(prepared by a known method disclosed in “Journal of the AmericanChemical Society, 2013, 135(30), 10934-10937”), accordingly, the titlecompound 78 (60 mg) was prepared.

MS m/z (ESI): 575.0 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, 2H), 7.82 (d, 1H), 7.73 (d, 2H),7.60 (dd, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 7.21-7.14 (m, 2H), 6.94 (d,1H), 6.82 (t, 1H), 6.31 (s, 1H), 5.91-5.87 (m, 1H), 3.75 (s, 3H), 3.48(s, 3H), 3.38 (d, 2H), 2.39 (s, 3H).

Example 794-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzoicacid 79

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 2-(bromomethyl)pyridine (prepared by aknown method disclosed in “Journal of the American Chemical Society,2016, 138(26), 8253-8258”), accordingly, the title compound 79 (370 mg)was prepared.

MS m/z (ESI): 546.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.72 (d, 1H), 8.29-8.25 (m, 1H), 8.00 (d, 2H),7.91 (d, 1H), 7.75-7.71 (m, 4H), 7.59 (dd, 1H), 7.35 (d, 1H), 7.25 (s,1H), 6.40 (s, 1H), 6.09-5.87 (m, 1H), 3.98-3.94 (m, 1H), 3.80-3.76 (m,1H), 3.59 (s, 3H), 2.56 (s, 3H).

Examples 80, 81(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzoicacid 80(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzoicacid 81

Compound 79 (370 mg, 677.69 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IF, 20*250 mm, 5 m;mobile phase: n-hexane:ethanol=50:50, flow rate: 10.0 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 80 (120 mg) and compound 81 (120mg).

Compound 80:

MS m/z (ESI): 546.2 [M+1]

Chiral HPLC analysis: retention time 9.971 minutes, (chromatographiccolumn: Lux Amylose-1 (AD) 4.6*150 mm, 5 μm (with a guard column);mobile phase: n-hexane/ethanol (containing 0.1% trifluoroaceticacid)=50/50 (v/v)).

Compound 81:

MS m/z (ESI): 546.2 [M+1]

Chiral HPLC analysis: retention time 6.219 minutes, (chromatographiccolumn: Lux Amylose-1 (AD) 4.6*150 mm, 5 m (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

Example 824-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-3-yl)propanamido)benzoicacid 82

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 3-(bromomethyl)pyridine (prepared by aknown method disclosed in “Chemical Communications (Cambridge, UnitedKingdom), 2016, 52(82), 12159-12162”), accordingly, the title compound82 (30 mg) was prepared.

MS m/z (ESI): 546.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.76-8.72 (m, 2H), 8.42 (d, 1H), 8.03-7.92 (m,5H), 7.76 (d, 2H), 7.62-7.59 (m, 1H), 7.37 (s, 2H), 6.36 (s, 1H),3.84-3.63 (m, 5H), 2.59 (s, 3H).

Examples 83, 84(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-3-yl)propanamido)benzoic acid 83(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-3-yl)propanamido)benzoicacid 84

Compound 82 (300 mg, 549.48 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IF, 20*250 mm, 5 μm;mobile phase: n-hexane:ethanol (containing 0.01% trifluoroaceticacid)=50:50, Flow rate: 12.0 mL/min). The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompound 83 (120 mg) and compound 84 (120 mg).

Compound 83:

MS m/z (ESI): 546.1 [M+1]

Chiral HPLC analysis: retention time 3.723 minutes, (chromatographiccolumn: CHIRAL PAK IF 4.6*150 mm, 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

Compound 84:

MS m/z (ESI): 546.1 [M+1]

Chiral HPLC analysis: retention time 7.315 minutes, (chromatographiccolumn: CHIRAL PAK IF 4.6*150 mm, 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.76-8.72 (m, 2H), 8.42 (d, 1H), 8.03-7.92 (m,5H), 7.76 (d, 2H), 7.62-7.59 (m, 1H), 7.37 (s, 2H), 6.36 (s, 1H),3.84-3.63 (m, 5H), 2.59 (s, 3H).

Example 85(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-2-yl)propanamido)benzamide85

In accordance with the synthetic route of Example 11, the startingcompound 5 was replaced with compound 80, accordingly, the titlecompound 85 (18 mg) was prepared.

MS m/z (ESI): 545.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, 1H), 7.88-7.84 (m, 3H), 7.78-7.74(dd, 1H), 7.72 (d, 2H), 7.57-7.55 (dd, 1H), 7.35-7.32 (m, 3H), 7.30-7.27(m, 1H), 6.39 (s, 1H), 6.06 (t, 1H), 3.79-3.74 (dd, 1H), 3.64-3.58 (m,4H), 2.49 (m, 3H).

Example 864-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-4-yl)propanamido)benzoicacid 86

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 4-(bromomethyl)pyridine hydrobromide(prepared by a known method disclosed in “Chemical Communications(Cambridge, United Kingdom), 2011, 47(5), 1482-1484”), accordingly, thetitle compound 86 (20 mg) was prepared.

MS m/z (ESI): 546.2 [M+1]

Example 874-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(2-cyanophenyl)propanamido)benzoicacid 87

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 2-(bromomethyl)benzonitrile (prepared by aknown method disclosed in “Journal of Organic Chemistry, 2014, 79 (23),11592-11608”), accordingly, the title compound 87 (15 mg) was prepared.

MS m/z (ESI): 570.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 10.69 (s, 1H), 7.92 (s, 1H),7.90 (s, 1H), 7.86-7.84 (d, 1H), 7.83 (m, 1H), 7.74 (s, 1H), 7.72 (s,1H), 7.64-7.60 (m, 2H), 7.45-7.41 (m, 2H), 7.39-7.38 (d, 1H), 7.30 (s,1H), 6.33 (s, 1H), 6.04-5.95 (m, 1H), 3.76-3.70 (m, 1H), 3.59-3.54 (m,1H), 3.51 (s, 3H), 2.43 (s, 3H).

Example 884-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-cyanophenyl)propanamido)benzoicacid 88

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with 3-(bromomethyl)benzonitrile (prepared by aknown method disclosed in “ChemMedChem, 2015, 10(4), 688-714”),accordingly, the title compound 88 (25 mg) was prepared.

MS m/z (ESI): 570.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 7.94-7.93 (m, 1H), 7.92-7.91(m, 1H), 7.86-7.84 (d, 1H), 7.77-7.68 (m, 4H), 7.62-7.60 (dd, 1H),7.59-7.57 (d, 1H), 7.52-7.48 (m, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 6.30(s, 1H), 6.04-6.00 (m, 1H), 3.62-3.50 (m, 5H), 2.41 (s, 3H).

Example 89(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3-cyanophenyl)propanamido)benzoicacid 89

Compound 88 (350 mg, 614.04 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IF, 20*250 mm; mobilephase: n-hexane:ethanol:trifluoroacetic acid=50:50:0.06, flow rate: 10.0mL/min), accordingly, the title compound 89 (60 mg) was prepared.

MS m/z (ESI): 570.1 [M+1]

Chiral HPLC analysis: retention time 12.723 minutes, (chromatographiccolumn: CHIRALPAK IE 150*4.6 mm, 5 m (with a guard column); mobilephase: n-hexane/ethanol (containing 0.01% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.01-8.00 (m, 1H), 7.98-7.97 (m, 1H),7.87-7.85 (d, 1H), 7.73-7.71 (m, 1H), 7.70-7.69 (m, 2H), 7.61-7.55 (m,3H), 7.50-7.46 (m, 1H), 7.38 (s, 1H), 7.34-7.33 (d, 1H), 6.39 (s, 1H),5.95-5.85 (m, 1H), 3.65-3.60 (m, 1H) 3.59 (s, 3H), 3.50-3.45 (m, 1H),2.46 (s, 3H).

Example 904-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-cyanophenyl)propanamido)benzoicacid 90

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 4-(bromomethyl)benzonitrile (prepared bya known method disclosed in “Organic & Biomolecular Chemistry, 2017,15(12), 2551-2561”), accordingly, the title compound 90 (15 mg) wasprepared.

MS m/z (ESI): 570.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 7.94-7.93 (m, 1H), 7.92-7.91(m, 1H), 7.85-7.83 (d, 1H), 7.77-7.74 (m, 4H), 7.62-7.59 (dd, 1H), 7.48(s, 1H), 7.45 (s, 1H), 7.40-7.39 (m, 1H), 7.38-7.36 (d, 1H), 6.29 (s,1H), 6.04-6.00 (m, 1H), 3.67-3.65 (m, 1H), 3.64-3.54 (m, 4H), 2.39 (s,3H).

Example 91 4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoic acid 91

Step 1 (1-cyclopropyl-1H-pyrazol-3-yl)methanol 91b

Ethyl 1-cyclopropyl-1H-pyrazol-3-carboxylate 91a (500 mg, 2.77 mmol,prepared by a method disclosed in the patent application“US20140349990”) was dissolved in 15 mL of tetrahydrofuran, and thenlithium aluminum hydride (527.18 mg, 13.87 mmol) was added at 0° C.After stirring for 1 hour at 0° C., the reaction solution was added with3 mL of sodium bicarbonate solution to quench the reaction, stirreduntil the gray solid disapperead, and filtered. The filtrate was driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude title compound 91b (300 mg), which was directly used inthe next reaction step without purification.

MS m/z (ESI): 139.2 [M+1]

Step 2 3-(bromomethyl)-1-cyclopropyl-1H-pyrazole 91c

The crude compound 91b (350 mg, 2.53 mmol) was dissolved indichloromethane (5 mL), and then phosphorus tribromide (2.06 g, 7.60mmol) was added dropwise. After stirring for 16 hours, the reactionsolution was added with 20 mL of saturated sodium bicarbonate solutionto quench the reaction, and extracted with dichloromethane (20 mL×3).The organic phases were combined, dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated under reduced pressure toobtain the crude title compound 91c (400 mg), which was directly used inthe next reaction step without purification.

Step 3 tert-butyl2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propionate 91d

Compound 8f (100 mg, 246.38 μmol) and the crude compound 91c (99.08 mg,492.77 μmol) were dissolved in 10 mL of tetrahydrofuran. After coolingto −78° C., the reaction solution was dropwise added with lithiumbis(trimethylsilyl)amide solution (0.985 mL, 985.53 μmol), and stirredfor 6 hours. At −78° C., the reaction solution was slowly added with 2mL of saturated ammonium chloride solution to quench the reaction, andthen warmed up to room temperature naturally. The reaction solution wasadded with 10 mL of water, and extracted with ethyl acetate (20 mL×3).The organic phases were combined, washed with saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 91d (90 mg, yield: 69.4%).

MS m/z (ESI): 526.2 [M+1]

Step 42-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propionicacid 91e

Compound 91d (90 mg, 171.1 μmol) was dissolved in 5 mL ofdichloromethane, and then trifluoroacetic acid (195.09 mg, 1.71 mmol)was added dropwise. After stirring for 2 hours, the reaction solutionwas concentrated under reduced pressure to obtain the crude titlecompound 91e (80 mg), which was directly used in the next reaction stepwithout purification.

MS m/z (ESI): 470.4 [M+1]

Step 544-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoicacid 91

The crude compound 91e (90 mg, 191.52 μmol) and the compound 8j (31.52mg, 229.83 μmol) were dissolved in 5 mL of ethyl acetate, followed bydropwise addition of N,N-diisopropylethylamine (123.76 mg, 957.62 μmol)and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 365.64 mg, 574.57 μmol). After completion of theaddition, the reaction solution was warmed up to 60° C., and stirred for2 hours. The reaction solution was added with 15 mL of water, andextracted with dichloromethane (15 mL×2). The organic phases werecombined, washed with saturated sodium chloride solution (15 mL×2),dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by high performance liquid chromatography (Waters 2767, elutionsystem: acetonitrile, water) to obtain the title compound 91 (50 mg,yield: 44.3%).

MS m/z (ESI): 589.3 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 8.13 (d, 2H), 7.85 (d, 2H), 7.70(d, 1H), 7.50 (d, 1H), 7.37 (d, 2H), 6.65 (s, 1H), 6.28 (s, 1H), 6.15(s, 1H), 3.77-3.42 (m, 6H), 2.91 (s, 2H), 1.18-1.15 (m, 3H), 1.10-1.05(m, 4H).

Example 92(S)-4-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclo propyl-1H-pyrazol-3-yl)propanamido)benzoic acid 92

Compound 91 (32 mg, 54.33 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 μm;mobile phase: n-hexane:ethanol (containing 0.01% trifluoroaceticacid)=40:60, flow rate: 10.0 mL/min). The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompound 92 (10 mg).

MS m/z (ESI): 589.2 [M+1]

Chiral HPLC analysis: retention time 13.016 min, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CDCl₃) δ 10.07 (s, 1H), 8.12 (d, 2H), 7.87 (d, 2H),7.70 (d, 1H), 7.50 (d, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 6.60 (s, 1H),6.25 (s, 1H), 6.12 (s, 1H), 3.72-3.68 (m, 4H), 3.59-3.58 (m, 1H),3.44-3.41 (m, 1H), 2.88-2.86 (m, 2H), 1.18-1.15 (m, 3H), 1.10-1.05 (m,4H).

Example 934-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoicacid 93

Step 1 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propionate93a

Compound 7b (100 mg, 255.20 μmol) and the crude compound 91c (102.62 mg,510.40 μmol) were dissolved in 10 mL of tetrahydrofuran. The reactionsolution was cooled to −78° C., and lithium bis(trimethylsilyl)amidesolution (1.02 mL, 1.02 mmol) was added dropwise. After stirring for 6hours, the reaction solution was slowly added with 2 mL of saturatedammonium chloride solution to quench the reaction, naturally warmed upto room temperature, added with 10 mL of water, and extracted with ethylacetate (20 mL×3). The organic phases were combined, washed withsaturated sodium chloride solution (20 mL×2) dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography with elution system B to obtain the title compound 93a(50 mg, yield: 38.3%).

MS m/z (ESI): 512.3 [M+1]

Step 22-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propionicacid 93b

Compound 93a (50 mg, 97.66 μmol) was dissolved in 5 mL ofdichloromethane, and then trifluoroacetic acid (111.35 mg, 976.57 μmol)was added dropwise. After stirring for 16 hours, the reaction solutionwas concentrated under reduced pressure to obtain the crude titlecompound 93b (45 mg), which was directly used in the next reaction stepwithout purification.

MS m/z (ESI): 456.2 [M+1]

Step 34-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoicacid 93

The crude compound 93b (45 mg, 98.71 μmol) and compound 8j (17.60 mg,128.32 μmol) were dissolved in 5 mL of ethyl acetate, followed bydropwise addition of N,N-diisopropylethylamine (63.79 mg, 493.54 μmol)and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 188.44 mg, 296.12 μmol) successively, Aftercompletion of the addition, the reaction solution was warmed up to 60°C. and stirred for 2 hours. After cooling to room temperature, thereaction solution was added with 15 mL of water, and extracted withdichloromethane (15 mL×2). The organic phases were combined, washed withsaturated sodium chloride solution (15 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by highperformance liquid chromatography (Waters 2767-SQ detecor2, elutionsystem: acetonitrile, water) to obtain the title compound 93 (50 mg,yield: 88.2%).

MS m/z (ESI): 575.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.86 (d, 1H), 7.73 (d, 2H),7.59-7.55 (m, 2H), 7.37 (d, 2H), 6.44 (s, 1H), 6.13 (s, 1H), 5.97-5.93(m, 1H), 3.64-3.47 (m, 5H), 3.16 (s, 1H), 2.51 (s, 3H), 1.02-0.98 (m,4H).

Examples 94, 95(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoicacid 94(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)propanamido)benzoicacid 95

Compound 93 (60 mg, 104.35 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 μm;mobile phase: n-hexane:ethanol (containing 0.01% trifluoroaceticacid)=30:70, flow rate: 7.0 mL/min). The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompound 94 (15 mg) and Compound 95 (15 mg).

Compound 94:

MS m/z (ESI): 575.2 [M+1]

Chiral HPLC analysis: retention time 15.655 min, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.86 (d, 1H), 7.73 (d, 2H),7.59-7.55 (m, 2H), 7.37 (d, 2H), 6.44 (s, 1H), 6.13 (s, 1H), 5.97-5.93(m, 1H), 3.64-3.47 (m, 5H), 3.16 (s, 1H), 2.51 (s, 3H), 1.02-0.98 (m,4H).

Compound 95:

MS m/z (ESI): 575.2 [M+1]

Chiral HPLC analysis: retention time 8.787 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.86 (d, 1H), 7.73 (d, 2H),7.59-7.55 (m, 2H), 7.37 (d, 2H), 6.44 (s, 1H), 6.13 (s, 1H), 5.97-5.93(m, 1H), 3.64-3.47 (m, 5H), 3.16 (s, 1H), 2.51 (s, 3H), 1.02-0.98 (m,4H).

Example 962-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)-N-(quinoxalin-6-yl)propanamide96

In accordance with the synthetic route of Example 93, the startingcompound 8j was replaced with 6-aminoquinoxaline (prepared by a methoddisclosed in the patent application “WO2013006792”), accordingly, thetitle compound 96 (35 mg) was prepared.

MS m/z (ESI): 583.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.80 (d, 2H), 8.55 (s, 1H), 8.06-7.98 (m, 2H),7.76 (dd, 1H), 7.58-7.53 (m, 1H), 7.51 (d, 1H), 7.43 (s, 1H), 7.30 (s,1H), 6.48 (s, 1H), 6.08 (s, 1H), 6.06-6.02 (m, 1H), 3.65 (s, 3H),3.60-3.53 (m, 2H), 3.44-3.41 (m, 1H), 2.51 (s, 3H), 1.02-0.98 (m, 4H).

Example 972-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-3-(l-cyclopropyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide97

In accordance with the synthetic route of Example 93, the startingcompound 8j was replaced with 18a, accordingly, the title compound 97(35 mg) was prepared.

MS m/z (ESI): 585.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.16 (s, 1H), 8.11 (s, 1H), 7.86 (d, 1H),7.59-7.55 (m, 3H), 7.42-7.33 (m, 3H), 6.46 (s, 1H), 6.15 (d, 1H),6.00-5.96 (m, 1H), 4.21 (s, 3H), 3.64 (s, 3H), 3.58-3.53 (m, 3H), 2.52(s, 3H), 1.02-0.98 (m, 4H).

Example 982-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-cyclopropyl-1H-pyrazol-3-yl)-N-(quinazolin-6-yl)propanamide98

In accordance with the synthetic route of Example 93, the startingcompound 8j was replaced with 23a, accordingly, the title compound 98(30 mg) was prepared.

MS m/z (ESI): 583.2 [M+1]

¹H NMR (400 MHz, MeOH-d₄) δ 9.50 (s, 1H), 8.19 (s, 1H), 8.62 (d, 1H),8.12 (d, 1H), 8.03 (d, 1H), 7.87 (d, 1H), 7.60-7.56 (m, 2H), 7.39-7.37(m, 2H), 6.46 (s, 1H), 6.15 (d, 1H), 6.00-5.96 (m, 1H), 3.64 (s, 3H),3.63-3.54 (m, 3H), 2.52 (s, 3H), 1.02-0.98 (m, 4H).

Example 994-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoicacid 99

In accordance with the synthetic route of Example 8, the startingcompound 8a was replaced with 3-(bromomethyl)-1-methyl-1H-pyrazole(prepared by a method disclosed in the patent application“WO2016045125”), accordingly, the title compound 99 (35 mg) wasprepared.

MS m/z (ESI): 563.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 8.13 (d, 2H), 7.87 (d, 2H),7.71-7.69 (m, 1H), 7.52-7.49 (m, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 6.64(s, 1H), 6.29-6.27 (m, 1H), 6.17 (d, 1H), 3.93 (s, 3H), 3.79-3.73 (m,4H), 3.47-3.45 (m, 1H), 2.91-2.89 (s, 2H), 1.19-1.15 (m, 3H).

Example 1004-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoicacid 100

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 3-(bromomethyl)-1-methyl-1H-pyrazole(prepared by a method disclosed in the patent application“WO2016045125”), accordingly, the title compound 100 (40 mg) wasprepared.

MS m/z (ESI): 549.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, 2H), 7.87 (d, 1H), 7.76-7.73 (m, 2H),7.60-7.59 (m, 1H), 7.58-7.57 (m, 1H), 7.39-7.37 (m, 2H), 6.46 (s, 1H),6.15 (d, 1H), 5.96-5.94 (m, 1H), 3.64 (s, 3H), 3.63 (s, 3H), 3.55-3.51(m, 1H), 3.49-3.46 (m, 1H), 2.52 (s, 3H).

Examples 101, 102(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoicacid 101(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanamido)benzoicacid 102

Compound 100 (40 mg, 72.86 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 μm;mobile phase: n-hexane:ethanol (containing 0.01% trifluoroaceticacid)=30:70, flow rate: 7.0 mL/min) The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompound 101 (15 mg) and compound 102 (15 mg).

Compound 101:

MS m/z (ESI): 549.2 [M+1]

Chiral HPLC analysis: retention time 16.341 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.12 (d, 2H), 7.87 (d, 2H),7.71 (d, 1H), 7.50 (d, 1H), 7.30-7.28 (m, 2H), 6.61 (s, 1H), 6.28-6.27(m, 1H), 6.13 (s, 1H), 3.88 (s, 3H), 3.72-3.68 (m, 1H), 3.67 (s, 3H),3.43-3.41 (m, 1H), 2.57 (s, 3H).

Compound 102:

MS m/z (ESI): 549.2 [M+1]

Chiral HPLC analysis: retention time 9.904 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.12 (d, 2H), 7.87 (d, 2H),7.71 (d, 1H), 7.50 (d, 1H), 7.30-7.28 (m, 2H), 6.61 (s, 1H), 6.28-6.27(m, 1H), 6.13 (s, 1H), 3.88 (s, 3H), 3.72-3.68 (m, 1H), 3.67 (s, 3H),3.43-3.41 (m, 1H), 2.57 (s, 3H).

Example 1034-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)benzoicacid 103

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 4-(bromomethyl)-1-methyl-1H-pyrazole(prepared by a method disclosed in the patent application “WO2015090599”), accordingly, the title compound 103 (40 mg) was prepared.

MS m/z (ESI): 549.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.12 (d, 2H), 7.90 (d, 2H), 7.75(d, 1H), 7.54-7.52 (m, 2H), 7.33-7.27 (m, 3H), 6.68 (s, 1H), 6.08 (s,1H), 3.92 (s, 3H), 3.65 (s, 3H), 3.48-3.43 (m, 1H), 3.24 (s, 1H), 2.57(s, 3H).

Examples 104, 105(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)benzoic acid 104(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)benzoicacid 105

Compound 103 (300 mg, 546.47 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 μm;mobile phase: ethanol (containing 0.01%)=100, flow rate: 7.0 mL/min).The corresponding fractions were collected and concentrated underreduced pressure to obtain the title compound 104 (120 mg) and compound105 (120 mg).

Compound 104:

MS m/z (ESI): 549.2 [M+1]

Chiral HPLC analysis: retention time 3.778 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol (containing 0.1% trifluoroacetic acid)=100).

¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 7.93-7.88 (m, 3H), 7.76 (d,2H), 7.65 (d, 1H), 7.48-7.45 (m, 3H), 7.25 (s, 1H), 6.37 (s, 1H),5.82-5.80 (m, 1H), 3.97 (s, 3H), 3.76 (s, 3H), 3.45-3.24 (m, 2H), 2.49(s, 3H).

Compound 105:

MS m/z (ESI): 549.2 [M+1]

Chiral HPLC analysis: retention time 5.535 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol (containing 0.1% trifluoroacetic acid)=100).

¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 7.93-7.88 (m, 3H), 7.76 (d,2H), 7.65 (d, 1H), 7.48-7.45 (m, 3H), 7.25 (s, 1H), 6.37 (s, 1H),5.82-5.80 (m, 1H), 3.97 (s, 3H), 3.76 (s, 3H), 3.45-3.24 (m, 2H), 2.49(s, 3H).

Example 1064-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(isoxazol-5-yl)propanamido)benzoic acid 106

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 5-bromomethylisoxazole (prepared by aknown method disclosed in “Journal of Medicinal Chemistry, 2016, 59(7),3471-3488”), accordingly, the title compound 106 (55 mg) was prepared.

MS m/z (ESI): 536.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H), 8.47-8.46 (s, 1H), 7.93-7.94(m, 1H), 7.92-7.91 (m, 1H), 7.86-7.85 (d, 1H), 7.77-7.76 (m, 1H),7.75-7.74 (m, 1H), 7.64-7.61 (dd, 1H), 7.44-7.43 (d, 1H), 7.38 (s, 1H),6.39 (s, 1H), 6.23-6.22 (d, 1H), 6.05-6.01 (m, 1H), 3.89-3.82 (m, 1H),3.73-3.71 (m, 1H), 3.52 (s, 3H), 2.45 (s, 3H)

Example 1074-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(thiazol-2-yl)propanamido)benzoicacid 107

In accordance with the synthetic route of Example 74, the startingcompound 74a was replaced with 2-bromomethylthiazole (prepared by amethod disclosed in the patent application “WO2014065413”), accordingly,the title compound 107 (20 mg) was prepared.

MS m/z (ESI): 551.9 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.98 (d, 2H), 7.86 (d, 1H), 7.75-7.71 (m, 3H),7.57 (dd, 1H), 7.52 (d, 1H), 7.37-7.36 (m, 2H), 6.47 (s, 1H), 6.06-6.02(m, 1H), 4.06-3.91 (m, 2H), 3.60 (s, 3H), 2.51 (s, 3H).

Examples 108, 109(S)-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoicacid 108(R)-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoicacid 109

Step 1 2-(tert-butoxy)ethyl trifluoromethanesulfonate 108b

2-tert-butoxyethanol 108a (300 mg, 2.54 mmol) was dissolved in 8 mL ofdichloromethane, and then 2,6-dimethylpyridine (299.22 mg, 2.79 mmol)was added in an ice bath, and trifluoromethanesulfonic anhydride (787.87mg, 2.79 mmol) was added dropwise. After completion of the addition, thereaction solution was stirred for 1 hour in an ice bath, naturallywarmed up to room temperature and stirred for 1 hour. The reactionsolution was added with 30 mL of dichloromethane, and washed with 20 mLof water. The organic phase was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to obtainthe crude title compound 108b (550 mg), which was directly used in thenext reaction step without purification.

Step 2 tert-butyl4-(tert-Butoxy)-2-(4-(5-chloro-2-prpionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyrate108c

Compound 8f (148 mg, 364.65 μmol) and the crude compound 108b (182.50mg, 729.30 μmol) were dissolved in 15 mL of tetrahydrofuran. Thereaction solution was cooled to −78° C., dropwise added with lithiumbis(trimethylsilyl)amide solution (1.46 mL, 1.46 mmol), and stirred for2 hours. The reaction solution was added with 5 mL of water at −78° C.to quench the reaction, naturally warmed up to room temperature, addedwith 20 mL of water, and extracted with etheyl acetate (35 mL×3). Theorganic phases were combined, washed with saturated sodium chloridesolution (25 mL×2), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem A to obtain the title compound 108c (120 mg, yield: 65.0%).

MS m/z (ESI): 506.5 [M+1]

Step 34-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyricacid 108d

Compound 108c (120 mg, 237.14 μmol) was dissolved in a mixed solvent of8 mL of ethanol and 4 mL of tetrahydrofuran, and lithium hydroxide(49.75 mg, 1.19 mmol) was added. The reaction solution was warmed up to50° C. and stirred for 2 hours. After cooling to room temperature, thereaction solution was concentrated under reduced pressure to remove mostof the organic solvents, added with 15 mL of water, added with 3Mhydrochloric acid to adjust the pH to 6, and extracted with ethylacetate (20 mL×3). The organic phases were combined, washed withsaturated sodium chloride (20 mL×2), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure to obtain the title compound 108d (106 mg), which was directlyused in the next reaction step without purification.

MS m/z (ESI): 450.4 [M+1]

Step 44-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoicacid 108e

The crude compound 108d (106 mg, 235.59 μmol) was dissolved in 15 mL ofethyl acetate, and then N,N-diisopropylethylamine (304.48 mg, 2.36mmol), compound 8j (35.54 mg, 259.16 μmol) and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 599.70 mg, 942.38 μmol) were added. After completionof the addition, the reaction solution was warmed up to 80° C., andstirred for 2 hours. After cooling to room temperature, the reactionsolution was added with 20 mL of water, added with 3M hydrochloric acidto adjust the pH to 5, and extracted with ethyl acetate (20 mL×3). Theorganic phases were combined, washed with saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure, and the resultingresidue was purified by high performance liquid chromatography (Waters2767-SQ detecor2, acetonitrile, water) to obtain the title compound 108e(60 mg, yield: 44.8%).

MS m/z (ESI): 569.5 [M+1]

Step 5(S)-4-(4-(tert-Butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-(2H)-yl)butanamido)benzoicacid 108(R)-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoicacid 109

Compound 108e (60 mg, 105.44 μmol) was separated chirally (separationconditions: chromatographic column Superchiral S-AD (Chiralway), 2 cmID*25 cm Length, 5 μm; mobile phase: carbondioxide:ethanol:diethylamine=60:40:0.05, flow rate: 50 g/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain title compound 108 (22 mg) and compound 109 (22 mg).

Compound 108:

MS m/z (ESI): 569.5 [M+1]

Chiral HPLC analysis: retention time 8.518 minutes, chiral purity 100%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 m (with a guardcolumn); mobile phase: n-hexane/ethanol (containing 0.1% trifluoroaceticacid)=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 10.73 (s, 1H), 7.90 (d, 2H),7.86 (d, 1H), 7.78 (d, 2H), 7.62 (dd, 1H), 7.41 (s, 1H), 7.27 (s, 1H),6.39 (s, 1H), 5.76-5.72 (m, 1H), 3.52 (s, 3H), 3.39-3.36 (m, 2H),2.99-2.86 (m, 2H), 2.36-2.27 (m, 2H), 1.06 (s, 9H), 1.00 (t, 3H).

Compound 109:

MS m/z (ESI): 569.4 [M+1]

Chiral HPLC analysis: retention time 5.172 minutes, chiral purity 99.7%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 m (with a guardcolumn); mobile phase: n-hexane/ethanol (containing 0.1% trifluoroaceticacid)=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 7.91-7.84 (m, 3H), 7.77 (d,2H), 7.62 (dd, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 6.39 (s, 1H), 5.76-5.72(m, 1H), 3.52 (s, 3H), 3.39-3.36 (m, 2H), 2.99-2.86 (m, 2H), 2.36-2.27(m, 2H), 1.06 (s, 9H), 1.00 (t, 3H).

Example 1104-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoicacid 110

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b,accordingly, the title compound 110 (30 mg) was prepared.

MS m/z (ESI): 555.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, 2H), 7.88 (d, 1H), 7.75 (d, 2H), 7.58(dd, 1H), 7.37 (d, 1H), 7.36 (s, 1H), 6.52 (s, 1H), 5.90-5.87 (m, 1H),3.65 (s, 3H), 3.57-3.43 (m, 2H), 2.55 (s, 3H), 2.49-2.36 (m, 2H), 1.18(s, 9H).

Examples 111, 112(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoicacid 111(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoicacid 112

Compound 110 (1.2 g, 2.16 mmol) was separated chirally (separationconditions: chromatographic column: Superchiral S-AD (Chiralway), 2 cmID*25 cm Length, 5 μm; mobile phase: carbondioxide:ethanol:diethylamine=60:40:0.05, flow rate: 50 g/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 111 (500 mg) and compound 112 (450mg).

Compound 111:

MS m/z (ESI): 555.1 [M+1]

Chiral HPLC analysis: retention time 16.803 minutes, chiral purity 100%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guardcolumn); mobile phase: n-hexane/ethanol (containing 0.1% trifluoroaceticacid)=70/30 (v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.03-7.99 (m, 2H), 7.89 (d, 1H), 7.76-7.74 (m,2H), 7.60 (dd, 1H), 7.39 (d, 1H), 7.36 (s, 1H), 6.52 (s, 1H), 5.91-5.87(m, 1H), 3.66 (s, 3H), 3.60-3.54 (m, 1H), 3.47-3.42 (m, 1H), 2.55 (s,3H), 2.52-2.45 (m, 1H), 2.42-2.37 (m, 1H), 1.18 (s, 9H).

Compound 112:

MS m/z (ESI): 555.1 [M+1]

Chiral HPLC analysis: retention time 4.247 minutes, chiral purity 100%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guardcolumn); mobile phase: n-hexane/ethanol (containing 0.1% trifluoroaceticacid)=70/30 (v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.03-7.99 (m, 2H), 7.89 (d, 1H), 7.76-7.74 (m,2H), 7.60 (dd, 1H), 7.39 (d, 1H), 7.36 (s, 1H), 6.52 (s, 1H), 5.91-5.87(m, 1H), 3.66 (s, 3H), 3.60-3.54 (m, 1H), 3.47-3.42 (m, 1H), 2.55 (s,3H), 2.52-2.45 (m, 1H), 2.42-2.37 (m, 1H), 1.18 (s, 9H).

Example 1134-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-N-(quinoxalin-6-yl)butanamide113

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j used in Step 4 was replaced with6-aminoquinoxaline (prepared by a method disclosed in the patentapplication “WO2013006792”), accordingly, the title compound 113 (35 mg)was prepared.

MS m/z (ESI): 577.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.85-8.83 (d, 1H), 8.80-8.79 (d, 1H),8.61-8.60 (m, 1H), 8.08-8.06 (d, 1H), 8.02-7.97 (dd, 1H), 7.85-7.83 (d,1H), 7.58-7.55 (dd, 1H), 7.40-7.35 (m, 2H), 6.50 (s, 1H), 5.95-5.85 (m,1H), 3.65-3.60 (m, 1H), 3.60-3.55 (s, 3H), 3.50-3.40 (m, 1H), 3.00-2.95(m, 2H), 2.50-2.40 (m, 1H), 2.35-2.25 (m, 1H), 1.17 (s, 9H), 1.10-1.00(m, 3H)

Examples 114, 115(S)-4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinoxalin-6-yl)butanamide114(R)-4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinoxalin-6-yl)butanamide115

Compound 113 (65 mg, 112.64 μmol) was separated chirally (separationconditions: chromatographic column Superchiral S-AD (Chiralway), 2.1 cmID*25 cm Length, 5 m; mobile phase:ethanol:acetonitrile:diethylamine=15:85:0.05, flow rate: 1.0 mL/min).The corresponding fractions were collected and concentrated underreduced pressure to obtain the title compound 114 (20 mg) and compound115 (20 mg).

Compound 114:

MS m/z (ESI): 577.3 [M+1]

Chiral HPLC analysis: retention time 17.031 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=30/70(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 10.50 (s, 1H), 8.85-8.83 (d, 1H), 8.80-8.79(d, 1H), 8.61-8.60 (m, 1H), 8.08-8.06 (d, 1H), 8.02-7.97 (dd, 1H),7.85-7.83 (d, 1H), 7.58-7.55 (dd, 1H), 7.40-7.35 (m, 2H), 6.50 (s, 1H),5.95-5.85 (m, 1H), 3.65-3.60 (s, 3H), 3.60-3.55 (m, 1H), 3.50-3.40 (m,1H), 3.00-2.95 (m, 2H), 2.50-2.40 (m, 1H), 2.35-2.25 (m, 1H), 1.17 (s,9H), 1.10-1.00 (m, 3H).

Compound 115:

MS m/z (ESI): 577.3 [M+1]

Chiral HPLC analysis: retention time 7.416 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=30/70(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 10.50 (s, 1H), 8.85-8.83 (d, 1H), 8.80-8.79(d, 1H), 8.61-8.60 (m, 1H), 8.08-8.06 (d, 1H), 8.02-7.97 (dd, 1H),7.85-7.83 (d, 1H), 7.58-7.55 (dd, 1H), 7.40-7.35 (m, 2H), 6.50 (s, 1H),5.95-5.85 (m, 1H), 3.65-3.60 (m, 1H), 3.60-3.55 (s, 3H), 3.50-3.40 (m,1H), 3.00-2.95 (m, 2H), 2.50-2.40 (m, 1H), 2.35-2.25 (m, 1H), 1.17 (s,9H), 1.10-1.00 (m, 3H).

Example 1162-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(1-oxoisoindolin-5-yl)butanamide116

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f used in Step 2 was replaced with the startingcompound 7b, and the starting compound 8j used in Step 4 was replacedwith 5-aminoisoindoline-1-one (prepared by a method disclosed in thepatent application “WO 2012092880”), accordingly, the title compound 116(35 mg) was prepared.

MS m/z (ESI): 566.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.04 (s, 1H), 7.89 (d, 1H), 7.76 (d, 1H), 7.65(d, 1H), 7.59 (d, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 6.52 (m, 1H),5.91-5.87 (m, 1H), 4.46 (s, 2H), 3.66 (s, 3H), 3.41-3.58 (m, 2H), 2.55(s, 3H), 2.30-2.51 (m, 2H), 1.18 (s, 9H).

Examples 117, 118(R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide117(S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide118

Step 1 tert-butyl(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)carbamate117b

5-((tert-Butoxycarbonyl)amino)-1H-indole-2-carboxylic acid 117a (4.5 g,16.29 mmol, prepared by a method disclosed in the patent application“WO2012162482”) was dissolved in 160 mL of tetrahydrofuran.N,N′-carbonyldiimidazole (5.82 g, 32.57 mmol) was added in an ice bath,and the mixture was warmed up to room temperature and stirred for 1.5hours. After cooling to 0° C., the reaction solution was dropwise addedwith cyclobutanone (2.85 g, 40.72 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (6.44 g, 42.35 mmol), and stirred for30 minutes at 0° C. The reaction solution was warmed up to roomtemperature, and stirred for 2 hours. The reaction solution wasconcentrated under reduced pressure to remove most of thetetrahydrofuran. The residue was poured into 150 mL of ice water, addedwith 3M hydrochloric acid to adjust the pH to about 5, and extractedwith ethyl acetate (50 mL×3). The organic phases were combined, washedwith saturated sodium chloride solution (40 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography with elution system B to obtain the title compound117b (2.7 g, yield: 50.5%).

MS m/z (ESI): 329.5 [M+1]

Step 2 7′-amino-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-1′-onehydrochloride 117c

Compound 117b (4.9 g, 14.92 mmol) was dissolved in 30 mL oftetrahydrofuran, and then 4M a solution of hydrogen chloride in1,4-dioxane (22.38 mL, 89.54 mmol) was added. The reaction solution waswarmed up to 45° C. and stirred for 5 hours. The reaction solution wasconcentrated under reduced pressure. The resulting residue was addedwith 40 mL of a mixed solvent of ethyl acetate and n-hexane (V/V=1:5),stirred, and filtered. The filter cake was collected to obtain the crudetitle compound 117c (3.9 g), which was directly used in the nextreaction step without purification.

MS m/z (ESI): 229.4 [M+1]

Step 3 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide117d

Compound 1g (400 mg, 1.02 mmol) was added to 12 mL ofN,N-dimethylformamide, followed by addition ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′tetramethyluroniumhexafluorophosphate (578.94 mg, 1.52 mmol), N,N-diisopropylethylamine(0.708 mL, 4.06 mmol) and the crude compound 117c (268.86 mg, 1.02mmol). After completion of the addition, the reaction solution washeated to 40° C. and stirred for 16 hours. The reaction solution wasadded with 50 mL of saturated sodium bicarbonate solution, and extractedwith ethyl acetate (100 mL×2). The organic phases were combined, washedwith saturated sodium chloride solution (50 mL×3), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelchromatography with elution system A to obtain the title compound 117d(400 mg, yield: 58.7%).

MS m/z (ESI): 604.5 [M+1]

Step 4(R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide117(S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy-N-(1′-oxo-1′H-spiro[cyclobutane-1,3′-oxazolo[3,4-a]indol]-7′-yl)butanamide118

Compound 117d (510 mg, 0.84 mmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 m;mobile phase: ethanol=100, flow rate: 8.0 mL/min). The correspondingfractions were collected and concentrated under reduced pressure toobtain the title compound 117 (150 mg) and compound 118 (135 mg).

Compound 117:

MS m/z (ESI): 604.6 [M+1]

Chiral HPLC analysis: retention time 8.666 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol).

¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 1H), 8.20 (s, 1H), 7.70-7.68 (d, 1H),7.54-7.49 (m, 2H), 7.48-7.47 (dd, 1H), 7.29-7.28 (d, 1H), 7.05 (s, 1H),7.00 (s, 1H), 6.67 (s, 1H), 5.95-5.80 (m, 1H), 3.60 (s, 3H), 3.57-3.54(m, 2H), 3.37 (s, 3H), 3.06-3.02 (m, 2H), 2.92-2.87 (m, 2H), 2.72-2.62(m, 1H), 2.50 (s, 3H), 2.35-2.15 (m, 3H).

Compound 118:

MS m/z (ESI): 604.5 [M+1]

Chiral HPLC analysis: retention time 11.473 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol).

¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 1H), 8.20 (s, 1H), 7.70-7.68 (d, 1H),7.54-7.49 (m, 2H), 7.48-7.47 (dd, 1H), 7.29-7.28 (d, 1H), 7.05 (s, 1H),7.00 (s, 1H), 6.67 (s, 1H), 5.95-5.80 (m, 1H), 3.60 (s, 3H), 3.57-3.54(m, 2H), 3.37 (s, 3H), 3.06-3.02 (m, 2H), 2.92-2.87 (m, 2H), 2.72-2.62(m, 1H), 2.50 (s, 3H), 2.35-2.15 (m, 3H).

Example 1195-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-1H-indole-2-carboxylicacid 119

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j was replaced with5-amino-1H-indole-2-carboxylic acid (prepared by a known methoddisclosed in “Journal of the American Chemical Society, 2006, 128 (37),12162-12168”), accordingly, the title compound 119 (20 mg) was prepared.

MS m/z (ESI): 608.6 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 10.25 (s, 1H), 7.96 (s, 1H),7.85 (d, 1H), 7.62 (dd, 1H), 7.41 (s, 1H), 7.35-7.28 (m, 3H), 6.80 (s,1H), 6.39 (s, 1H), 5.78-5.74 (m, 1H), 3.52 (s, 3H), 3.29-3.25 (m, 2H),2.98-2.85 (m, 2H), 2.35-2.23 (m, 2H), 1.08 (s, 9H), 1.00 (t, 3H).

Example 12044-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzoicacid 120

Step 12-(4-(6-Acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-(2H)-yl)acetate120a

Compound 30c (300 mg, 1.01 mmol), compound 7a (217.68 mg, 1.12 mmol) andcesium carbonate (661.13 mg, 2.03 mmol) were dissolved in 10 mL ofN,N-dimethylformamide. The reaction solution was warmed up to 65° C. andstirred for 2 hours. After cooling to room temperature, the reactionsolution was added with 20 mL of water, and extracted with ethyl acetate(20 mL×3). The organic phases were combined, washed with saturatedsodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated under reduced pressure, andthe resulting residue was purified by silica gel column chromatographywith elution system C to obtain the title compound 120a (300 mg, yield:72.1%).

MS m/z (ESI): 410.4 [M+1]

Step 2 to Step 4

In accordance with the synthetic route of the compound 108e in Example108, the starting compound 8f was replaced with 120a, accordingly, thetitle compound 120 (35 mg) was prepared.

MS m/z (ESI): 573.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 7.91-7.89 (m, 2H), 7.83-7.76(m, 4H), 7.37 (d, 1H), 6.40 (d, 1H), 5.82-5.76 (m, 1H), 3.59 (s, 3H),3.41-3.36 (m, 1H), 3.29-3.23 (m, 1H), 2.47 (d, 3H), 2.38-2.32 (m, 2H),1.04 (d, 9H).

Example 1214-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinazolin-6-yl)butanamide121

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j was replaced with compound 23a, accordingly,the title compound 121 (20 mg) was prepared.

MS m/z (ESI): 577.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.93 (dd, 1H), 7.87 (d, 1H),7.80-7.73 (m, 1H), 7.60 (dd, 1H), 7.39-7.38 (m, 1H), 7.34 (s, 1H), 7.31(d, 1H), 6.51 (s, 1H), 6.21 (s, 1H), 5.83-5.78 (m, 1H), 3.65 (s, 3H),3.58-3.40 (m, 2H), 3.03-2.97 (m, 2H), 2.54-2.40 (m, 2H), 1.18 (s, 9H),1.12 (t, 3H).

Example 122(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)benzamide122

In accordance with the synthetic route of Example 11, the startingcompound 5 was replaced with compound 111, accordingly, the titlecompound 122 (40 mg) was prepared.

MS m/z (ESI): 554.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H), 7.90-7.83 (m, 4H), 7.73 (d,2H), 7.63 (dd, 1H), 7.42 (s, 1H), 7.29-7.27 (m, 2H), 6.41 (s, 1H),5.79-5.76 (m, 1H), 3.55 (s, 3H), 3.30-3.28 (m, 2H), 2.55 (s, 3H),2.36-2.28 (m, 2H), 1.07 (s, 9H).

Example 123(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)butanamido)-N-methylbenzamide123

In accordance with the synthetic route of Example 13, the startingcompound 5 was replaced with compound 111, accordingly, the titlecompound 123 (40 mg) was prepared.

MS m/z (ESI): 568.1 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.73 (br, 1H), 7.76-7.65 (m, 4H), 7.51 (d,1H), 7.32-7.31 (m, 1H), 6.98 (s, 1H), 6.66 (s, 1H), 6.26-6.24 (m, 1H),5.84-5.79 (m, 1H), 3.62 (s, 3H), 3.54-3.52 (m, 2H), 3.03 (d, 1H),2.66-2.61 (m, 1H), 2.53 (s, 3H), 2.33-2.25 (m, 2H), 1.20 (s, 9H).

Example 1244-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-N-(2,3-dimethylquinoxalin-6-yl)butanamide124

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j used in Step 4 was replaced with2,3-dimethyl-6-quinoxalinamine (prepared by a known method disclosed in“Bioorganic & Medicinal Chemistry Letters, 2012, 20(7), 2227-2234”),accordingly, the title compound 124 (15 mg) was prepared.

MS m/z (ESI): 605.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.45-8.42 (d, 1H), 7.92-7.90 (d, 1H),7.90-7.86 (dd, 1H), 7.85-7.82 (d, 1H), 7.57-7.52 (dd, 1H), 7.37 (s, 2H),6.50 (s, 1H), 5.95-5.85 (m, 1H), 3.65-3.60 (s, 3H), 3.60-3.55 (m, 1H),3.50-3.40 (m, 1H), 3.00-2.95 (m, 2H), 2.70 (s, 6H), 2.50-2.40 (m, 1H),2.35-2.25 (m, 1H), 1.17 (s, 9H), 1.10-1.00 (m, 3H).

Example 1254-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-N-(2-cyano-1H-indol-6-yl)butanamide125

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j was replaced with6-amino-1H-indole-2-carbonitrile (prepared according to the patentapplication “US20160271105”), accordingly, the title compound 125 (30mg) was prepared.

MS m/z (ESI): 589.5 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.04 (s, 1H), 7.85-7.83 (d, 1H), 7.61-7.59 (d,1H), 7.58-7.57 (dd, 1H), 7.38-7.37 (d, 1H), 7.36 (s, 1H), 7.25-7.18 (dd,1H), 7.16-7.15 (d, 1H), 6.50 (s, 1H), 5.95-5.90 (m, 1H), 3.63 (s, 3H),3.60-3.55 (m, 1H), 3.50-3.40 (m, 1H), 3.00-2.95 (m, 2H), 2.50-2.40 (m,1H), 2.35-2.25 (m, 1H), 1.17 (s, 9H), 1.10-1.00 (m, 3H).

Example 126N-(Benzo[d]thiazol-5-yl)-4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamide126

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j was replaced with benzo[d]thiazol-5-amine(prepared according to the patent application “WO2013142266”),accordingly, the title compound 126 (35 mg) was prepared.

MS m/z (ESI): 582.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 8.50 (s, 1H), 8.03-8.00 (d, 1H),7.84-7.82 (d, 1H), 7.68-7.69 (d, 1H), 7.57-7.54 (dd, 1H), 7.38-7.35 (m,2H), 6.50 (s, 1H), 5.95-5.85 (m, 1H), 3.62 (s, 3H), 3.60-3.55 (m, 1H),3.50-3.40 (m, 1H), 3.00-2.80 (m, 2H), 2.50-2.40 (m, 1H), 2.35-2.25 (m,1H), 1.17 (s, 9H), 1.11-1.09 (m, 3H).

Example 1274-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)thiophene-2-carboxylicacid 127

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j was replaced with 4-aminothiophene-2-carboxylicacid (prepared according to the patent application “Journal of theAmerican Chemical Society, 1999, 121 (34), 7751-7759”), accordingly, thetitle compound 127 (20 mg) was prepared.

MS m/z (ESI): 575.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.85 (s, 1H), 7.85-7.84 (d, 1H), 7.82-7.80 (d,1H), 7.58-7.55 (d, 1H), 7.38-7.36 (d, 1H), 7.33-7.31 (s, 1H), 6.48 (s,1H), 5.95-5.85 (m, 1H), 3.65-3.60 (m, 3H), 3.60-3.55 (m, 1H), 3.50-3.40(m, 1H), 3.00-2.95 (m, 2H), 2.50-2.40 (m, 1H), 2.35-2.25 (m, 1H), 1.17(s, 9H), 1.10-1.00 (m, 3H).

Example 128 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)butanamide128

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (prepared by a known methoddisclosed in “Bioorganic & Medicinal Chemistry Letters, 2015, 25 (10),2122-2128”), accordingly, the title compound 128 (23 mg) was prepared.

MS m/z (ESI): 568.1 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.69 (d, 1H), 7.51-7.48 (dd,1H), 7.32 (d, 1H), 7.07 (d, 1H), 6.95 (s, 1H), 6.75-6.71 (m, 2H), 6.60(s, 1H), 5.80 (s, 1H), 4.25 (t, 2H), 3.59 (s, 3H), 3.52 (t, 2H), 3.43(t, 2H), 2.63-2.59 (m, 1H), 2.50 (s, 3H), 2.22-2.18 (m, 1H), 1.22 (s,9H).

Example 129 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3-fluorophenyl)butanamide 129

In accordance with the synthetic route of the compound 108e in Example108, the starting compound 8f was replaced with the starting compound7b, and the starting compound 8j was replaced with 3-fluoroaniline,accordingly, the title compound 129 (20 mg) was prepared.

MS m/z (ESI): 529.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.67 (br, 1H), 8.01-8.00 (m, 1H), 7.75-7.70(m, 2H), 7.52-7.45 (m, 2H), 7.40-7.38 (m, 1H), 7.34-7.33 (m, 1H), 6.91(s, 1H), 6.64 (s, 1H), 5.79 (br, 1H), 3.61 (s, 3H), 3.56-3.53 (m, 2H),2.70-2.62 (m, 1H), 2.53 (s, 3H), 2.27-2.23 (m, 1H), 1.22 (m, 9H).

Example 130 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(5-chloropyridin-3-yl)butanamide 130

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 5-chloropyridin-3-amine(prepared by a method disclosed in the patent application“WO2006067445”), accordingly, the title compound 130 (25 mg) wasprepared.

MS m/z (ESI): 546.0 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.68 (d, 1H), 8.33 (m, 1H), 8.31 (d, 1H), 7.89(d, 1H), 7.58 (dd, 1H), 7.38 (d, 1H), 7.33 (s, 1H), 6.51 (s, 1H),5.86-5.81 (m, 1H), 3.65 (s, 3H), 3.58-3.40 (m, 2H), 2.56 (s, 3H),2.53-2.39 (m, 2H), 1.18 (s, 9H).

Example 131 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(5-fluoropyridin-3-yl)butanamide 131

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 5-fluoropyridin-3-amine(prepared by a known method disclosed in “Journal of MedicinalChemistry, 1999, 42 (18), 3701-3710”), accordingly, the title compound131 (25 mg) was prepared.

MS m/z (ESI): 530.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 8.24 (d, 1H), 8.18-8.14 (m, 1H),7.89 (d, 1H), 7.59 (dd, 1H), 7.38 (d, 1H), 7.33 (s, 1H), 6.51 (s, 1H),5.86-5.81 (m, 1H), 3.65 (s, 3H), 3.58-3.40 (m, 2H), 2.56 (s, 3H),2.53-2.39 (m, 2H), 1.18 (s, 9H).

Example 132 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(4-fluorophenyl)butanamide 132

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f used in Step 2 was replaced with the startingcompound 7b, and the starting compound 8j used in Step 4 was replacedwith 4-fluoroaniline, accordingly, the title compound 132 (20 mg) wasprepared.

MS m/z (ESI): 529.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.37 (br, 1H), 7.72-7.70 (d, 1H), 7.59-7.56(m, 2H), 7.52-7.49 (m, 1H), 7.33-7.32 (m, 1H), 7.07-7.02 (m, 2H), 6.95(s, 1H), 6.62 (s, 1H), 5.78 (br, 1H), 3.60 (s, 3H), 3.54-3.52 (m, 2H),2.66-2.60 (m, 1H), 2.52 (s, 3H), 2.26-2.21 (m, 1H), 1.22 (m, 9H).

Example 133 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)butanamide133

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (prepared by a known methoddisclosed in “Journal of Medicinal Chemistry, 2005, 48(1), 71-90”),accordingly, the title compound 133 (19 mg) was prepared.

MS m/z (ESI): 568.5 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 7.69 (d, 1H), 7.50-7.48 (dd,1H), 7.32 (d, 1H), 7.09 (d, 1H), 6.97 (s, 1H), 6.94 (d, 1H), 6.60 (s,1H), 6.56 (d, 1H), 5.78 (s, 1H), 4.26 (t, 2H), 3.59 (s, 3H), 3.42 (t,2H), 3.51 (t, 2H), 2.60-2.57 (m, 1H), 2.50 (s, 3H), 2.27-2.24 (m, 1H),1.22 (s, 9H).

Example 134 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(6-methoxypyridin-3-yl)butanamide 134

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 6-methoxypyridin-3-amine(prepared by a known method disclosed in “Tetrahedron Letters, 2010, 51(5), 786-789”), accordingly, the title compound 134 (25 mg) wasprepared.

MS m/z (ESI): 542.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.95-7.91 (m, 1H), 7.89 (d, 1H),7.59 (dd, 1H), 7.38 (d, 1H), 7.34 (s, 1H), 6.83 (d, 1H), 6.52 (s, 1H),5.85-5.82 (m, 1H), 3.91 (s, 3H), 3.65 (s, 3H), 3.58-3.40 (m, 2H), 2.55(s, 3H), 2.51-2.33 (m, 2H), 1.19 (s, 9H).

Example 135 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3-(trifluoromethyl)phenyl)butanamide 135

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 3-(trifluoromethyl)aniline(prepared by a known method disclosed in “Journal of Organic Chemistry,2016, 81 (12), 5120-5127”), accordingly, the title compound 135 (15 mg)was prepared.

MS m/z (ESI): 579.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.53 (br, 1H), 7.72-7.70 (m, 1H), 7.61-7.58(m, 1H), 7.52-7.49 (m, 1H), 7.33-7.32 (m, 1H), 7.30-7.21 (m, 2H), 6.92(s, 1H), 6.86-6.82 (m, 1H), 6.63 (s, 1H), 5.78 (br, 1H), 3.60 (s, 3H),3.55-3.52 (m, 2H), 2.68-2.60 (m, 1H), 2.52 (s, 3H), 2.26-2.21 (m, 1H),1.22 (s, 9H).

Example 136 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(4-(trifluoromethyl)phenyl)butanamide 136

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 4-(trifluoromethyl)aniline(prepared by a known method disclosed in “Journal of Organic Chemistry,2009, 74 (12), 4542-4546”), accordingly, the title compound 136 (20 mg)was prepared.

MS m/z (ESI): 579.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.70 (br, 1H), 7.76-7.72 (m, 3H), 7.62-61 (m,2H), 7.52-7.51 (m, 1H), 7.34-7.32 (m, 1H), 6.92-6.90 (m, 1H), 6.65-6.63(m, 1H), 5.80-5.77 (m, 1H), 3.61-3.60 (m, 3H), 3.54 (br, 2H), 2.67-2.66(m, 1H), 2.54-2.52 (m, 3H), 2.28-2.24 (m, 1H), 1.23-1.21 (m, 9H).

Example 137 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)butanamide137

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with2,3-dihydrobenzo[b][1,4]dioxin-5-amine (prepared by a method disclosedin the patent application “WO2012092880”), accordingly, the titlecompound 137 (30 mg) was prepared.

MS m/z (ESI): 569.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.90 (d, 1H), 7.69 (d, 1H), 7.48(d, 1H), 7.33 (d, 1H), 7.00 (s, 1H), 6.82 (t, 1H), 6.67 (dd, 1H), 6.61(s, 1H), 5.89-5.85 (m, 1H), 4.42-4.39 (m, 2H), 4.32-4.30 (m, 2H), 3.60(s, 3H), 3.52-3.49 (m, 2H), 2.61-2.57 (m, 1H), 2.51 (s, 3H), 2.25-2.12(m, 1H), 1.21 (m, 9H).

Example 138 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)butanamide138

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (prepared by a known methoddisclosed in “Journal of Medicinal Chemistry, 2017, 60 (6), 2401-2410”),accordingly, the title compound 138 (21 mg) was prepared.

MS m/z (ESI): 568.1 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 7.70 (d, 1H), 7.52-7.49 (dd,1H), 7.32 (d, 1H), 7.13-7.11 (m, 1H), 6.94 (s, 1H), 6.72-6.70 (m, 2H),6.61 (s, 1H), 5.70 (s, 1H), 4.23-4.19 (m, 2H), 3.60 (s, 3H), 3.58-3.55(m 2H), 3.48 (s, 2H), 2.68-2.62 (m, 1H), 2.52 (s, 3H), 2.28-2.22 (m,1H), 1.23 (s, 9H).

Example 139 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanamide139

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with2,3-dihydrobenzo[b][1,4]dioxin-6-amine (prepared by a well-known methoddisclosed in “Chemical Communications, 2012, 48 (64), 7982-7984”),accordingly, the title compound 139 (30 mg) was prepared.

MS m/z (ESI): 569.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.33(s, 1H), 7.26 (s, 1H), 6.98 (d, 1H), 6.94 (s, 1H), 6.82 (d, 1H), 6.61(s, 1H), 5.78-5.77 (m, 1H), 4.27 (s, 4H), 3.60 (s, 3H), 3.51-3.52 (m,2H), 2.61-2.62 (m, 1H), 2.51 (s, 3H), 2.22-2.26 (s, 1H), 1.22 (m, 9H).

Example 1402-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(benzo[d][1,3]dioxol-5-yl)-4-(tert-butoxy)butanamide140

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f used in Step 2 was replaced with the startingcompound 7b, and the starting compound 8j used in Step 4 was replacedwith benzo[d][1,3]dioxol-5-amine (prepared by a method disclosed in thepatent application “CN105348251”), accordingly, the title compound 140(25 mg) was prepared.

MS m/z (ESI): 555.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.89 (d, 1H), 7.59 (d, 1H), 7.39 (s, 1H), 7.35(s, 1H), 7.06 (s, 1H), 6.97 (d, 1H), 6.79 (d, 1H), 6.52 (s, 1H),5.85-5.81 (m, 1H), 3.65 (s, 3H), 3.55-3.42 (m, 2H), 2.55 (s, 3H),2.44-2.34 (m, 2H), 1.19 (s, 9H).

Example 1414-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-N-(2-methyl-2H-carbazol-5-yl)butanamide141

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8j was replaced with compound 18a, accordingly,the title compound 141(25 mg) was prepared.

MS m/z (ESI): 579.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.89 (d, 1H), 7.60 (d, 1H), 7.41-7.39 (m, 2H),7.35 (s, 1H), 7.21 (d, 1H), 7.12 (d, 1H), 6.52 (s, 1H), 5.87-5.84 (m,1H), 3.66 (s, 3H), 3.62-3.52 (m, 1H), 3.51 (s, 2H), 3.47-3.43 (m, 1H),2.55 (s, 3H), 2.53-2.37 (m, 2H), 1.35-1.31 (m, 2H), 1.19 (s, 9H).

Example 1422-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(1H-indol-4-yl)butanamide142

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 1H-indole-4-amine (preparedby a known method disclosed in “Journal of Medicinal Chemistry, 2005, 48(9), 3417-3427”), accordingly, the title compound 142 (25 mg) wasprepared.

MS m/z (ESI): 550.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.89 (d, 1H), 7.59 (d, 1H), 7.45 (d, 1H), 7.40(s, 1H), 7.38 (d, 2H), 7.28-7.26 (m, 2H), 7.10 (t, 1H), 6.63-6.61 (m,1H), 6.57 (s, 1H), 6.03-5.99 (m, 1H), 3.66 (s, 3H), 3.62-3.47 (m, 2H),2.55 (s, 3H), 2.54-2.40 (m, 2H), 1.20 (s, 9H).

Example 1432-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)butanamide143

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with6-amino-3,4-dihydroisoquinolin-1(2H)-one (prepared by a method disclosedin the patent application “CN103804358”), accordingly, the titlecompound 143 (20 mg) was prepared.

MS m/z (ESI): 580.6 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 1H), 8.05 (d, 1H), 7.70 (d, 1H), 7.64(d, 1H), 7.51-7.47 (m, 2H), 7.32 (d, 1H), 6.91 (s, 1H), 6.62 (s, 1H),5.91 (s, 1H), 5.79 (s, 1H), 3.60 (s, 3H), 3.59-3.52 (m, 4H), 3.01 (t,2H), 2.68-2.60 (m, 1H), 2.52 (s, 3H), 2.28-2.20 (m, 1H), 1.22 (s, 9H).

Example 1442-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2-oxoindolin-6-yl)butanamide144

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 6-aminoindol-2-one (preparedby a method disclosed in the patent application “WO2009079767”),accordingly, the title compound 144 (25 mg) was prepared.

MS m/z (ESI): 566.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 1H), 8.13 (s, 1H), 7.86 (d, 1H),7.60-7.57 (m, 2H), 7.39-7.37 (m, 3H), 6.52 (s, 1H), 5.90-5.86 (m, 1H),4.21 (s, 3H), 3.65 (s, 3H), 3.58-3.46 (m, 2H), 2.98 (s, 2H), 2.47-2.32(m, 2H), 1.20 (s, 9H).

Example 145 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-(tert-butoxy)-N-(2-oxoindolin-5-yl)butanamide 145

In accordance with the synthetic route of compound 108e in Example 108,the starting compound 8f was replaced with the starting compound 7b, andthe starting compound 8j was replaced with 5-aminoindol-2-one (preparedby a known method disclosed in “Bioorganic and Medicinal Chemistry,2013, 21 (7), 1724-1734”), accordingly, the title compound 145 (25 mg)was prepared.

MS m/z (ESI): 566.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.89 (d, 1H), 7.59 (d, 1H), 7.56 (s, 1H),7.41-7.39 (m, 2H), 7.36 (s, 1H), 6.87 (d, 1H), 6.51 (s, 1H), 5.87-5.82(m, 1H), 3.65 (s, 3H), 3.55 (s, 2H), 3.54-3.43 (m, 2H), 2.55 (s, 3H),2.53-2.36 (m, 2H), 1.19 (s, 9H).

Example 1464-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(21)-yl)-4-methoxvbutanamido)benzoicacid 146

In accordance with the synthetic route in Example 30, the startingcompound 4a was replaced with compound 1b, accordingly, the titlecompound 146 (35 mg) was prepared.

MS m/z (ESI): 531.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.03-7.99 (m, 2H), 7.78-7.68 (m, 4H), 7.46 (d,1H), 6.51 (s, 1H), 5.89-5.77 (m, 1H), 3.69 (d, 3H), 3.58-3.53 (m, 1H),3.47-3.40 (m, 1H), 3.36 (s, 3H), 2.59-2.51 (m, 4H), 2.44-2.38 (m, 1H).

Example 1474-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)benzoicacid 147

In accordance with the synthetic route in Example 1, the startingcompound 1h was replaced with compound 4c, accordingly, the titlecompound 147 (20 mg) was prepared.

MS m/z (ESI): 513.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 7.89-7.87 (m, 3H), 7.76 (s,1H), 7.74 (s, 1H), 7.64-7.61 (dd, 1H), 7.46-7.45 (d, 1H), 7.29 (s, 1H),6.40 (s, 1H), 5.72-5.70 (m, 1H), 3.53 (s, 3H), 3.27-3.25 (m, 2H), 3.22(s, 3H), 2.50 (s, 3H), 2.33-2.30 (m, 2H).

Example 1484-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-2-fluorobenzoicacid 148

In accordance with the synthetic route of Example 1, the startingcompound 1h was replaced with methyl 4-amino-2-fluorobenzoate (preparedby a method disclosed in the patent application “WO2013068467”),accordingly, the title compound 148 (15 mg) was prepared.

MS m/z (ESI): 531.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.89-7.87 (d, 1H), 7.76-7.72(m, 1H), 7.64-7.62 (dd, 1H), 7.61-7.58 (d, 1H), 7.47-7.45 (d, 1H),7.40-7.38 (d, 1H), 7.28 (s, 1H), 6.40 (s, 1H), 5.72-5.70 (m, 1H), 3.53(s, 3H), 3.27-3.25 (m, 2H), 3.22 (s, 3H), 2.50 (s, 3H), 2.33-2.30 (m,2H).

Example 1494-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-2-methoxybenzoicacid 149

In accordance with the synthetic route of Example 1, the startingcompound 1h was replaced with methyl 4-amino-2-methoxybenzoate (preparedby a method disclosed in the patent application “WO 2016053794”),accordingly, the title compound 149 (42 mg) was prepared.

MS m/z (ESI): 543.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.67 (s, 1H), 7.89 (d, 1H), 7.63 (d, 2H),7.53 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 7.23 (d, 1H), 6.41 (s, 1H),5.74-5.70 (m, 1H), 3.77 (s, 3H), 3.54 (s, 3H), 3.30-3.27 (m, 2H), 3.22(s, 3H), 2.53 (s, 3H), 2.38-2.36 (m, 2H)

Example 1502-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-methoxybutanamide150

In accordance with the synthetic route of Example 117, the startingcompound 117c was replaced with6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (prepared by amethod disclosed in the patent application “JP 2008013527”),accordingly, the title compound 150 (40 mg) was prepared.

MS m/z (ESI): 566.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H), 10.42 (s, 1H), 7.89-7.87 (d,1H), 7.64-7.62 (dd, 1H), 7.47-7.46 (d, 1H), 7.39-7.38 (d, 1H), 7.29 (s,1H), 7.12-7.09 (dd, 1H), 6.88-6.86 (d, 1H), 6.40 (s, 1H), 5.72-5.70 (m,1H), 3.53 (s, 3H), 3.27-3.25 (m, 2H), 3.22 (s, 3H), 2.50 (s, 3H),2.33-2.30 (m, 2H), 1.37 (s, 6H)

Example 151 1-((ethoxycarbonyl)oxy)ethyl5-((R)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate151 1-((ethoxycarbonyl)oxy)ethyl5-((S)-2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate152

In accordance with the synthetic route of Examples 14, 15, the startingcompound 14a was replaced with 5-nitro-1H-indole-2-carboxylic acid(prepared by a method disclosed in the patent application“US20160282369”), the starting compound 14b was replaced with1-chloroethylethyl carbonate (prepared by a known method disclosed in“Tetrahedron Letters, 2016, 57 (14), 1619-1621”), and the startingcompound 4b was replaced with compound 1g. After chiral speration(separation conditions: chromatographic column Superchiral S-AD(Chiralway), 2 cm ID*25 cm Length, 5 μm; mobile phase: carbondioxide:isopropanol=70:30, flow rate: 50 g/min), the correspondingfractions were collected and concentrated under reduced pressure toobtain the title compounds 151 (90 mg) and 152 (96 mg).

Compound 151:

MS m/z (ESI): 668.6 [M+1]

Chiral HPLC analysis: retention time 25.596 minutes, chiral purity 99.3%(chromatographic column: Lux® Amylose-1 (AD) 4.6*150 mm 5 μm (with aguard column); flow rate: 1 mL/min; mobile phase: ethanol/n-hexane=50/50(v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 10.41 (s, 1H), 10.22 (s, 1H),8.09 (s, 1H), 7.90-7.88 (d, 1H), 7.64-7.61 (dd, 1H), 7.48-7.46 (d, 1H),7.44-7.40 (m, 1H), 7.34 (s, 1H), 7.21-7.20 (d, 1H), 6.93-6.89 (m, 1H),6.40 (s, 1H), 5.80-5.70 (m, 1H), 4.19-4.14 (m, 2H), 3.55 (s, 3H),3.27-3.25 (m, 2H), 3.23 (s, 3H), 2.50 (s, 3H), 2.40-2.30 (m, 2H), 1.60(d, 3H), 1.24-1.20 (m, 3H)

Compound 152:

MS m/z (ESI): 668.5 [M+1]

Chiral HPLC analysis: retention time 11.905 minutes, chiral purity 100%(chromatographic column: Lux® Amylose-1 (AD) 4.6*150 mm 5 μm (with aguard column); flow rate: 1 mL/min; mobile phase: ethanol/n-hexane=50/50(v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 10.41 (s, 1H), 10.22 (s, 1H),8.09 (s, 1H), 7.90-7.88 (d, 1H), 7.64-7.61 (dd, 1H), 7.48-7.46 (d, 1H),7.44-7.40 (m, 1H), 7.34 (s, 1H), 7.21-7.20 (d, 1H), 6.93-6.89 (m, 1H),6.40 (s, 1H), 5.80-5.70 (m, 1H), 4.19-4.14 (m, 2H), 3.55 (s, 3H),3.27-3.25 (m, 2H), 3.23 (s, 3H), 2.50 (s, 3H), 2.40-2.30 (m, 2H), 1.60(d, 3H), 1.24-1.20 (m, 3H)

Examples 153, 154 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(R)-5-(2-(4-(2-acetyl-5-chlorophenyl))-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate153 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(S)-5-(2-(4-(2-acetyl-5-chlorophenyl))-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanamido)-1H-indole-2-carboxylate154

In accordance with the synthetic route of Examples 14, 15, the startingcompound 14a was replaced with5-((tert-butoxycarbonyl)amino)-1H-indole-2-carboxylic acid (prepared bya known method disclosed in “Journal of the American Chemical Society,2007, 129 (17), 5384-5390”), the starting compound 14b is replaced with4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (prepared by a methoddisclosed in the patent application “CN103450146”), and the startingcompound 4b is replaced with the compound 1g. After chiral speration(separation conditions: chiral preparation column CHIRAL PAK IE, 20*250mm, 5 m; mobile phase: methanol:ethanol=50:50, flow rate: 10 mL/min),the corresponding fractions were collected and concentrated underreduced pressure to obtain the title compounds 153 (60 mg) and 154 (25mg).

Compound 153:

MS m/z (ESI): 664.5 [M+1]

Chiral HPLC analysis: retention time 7.129 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); flow rate:1 mL/min; mobile phase: methanol/ethanol=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.39 (s, 1H), 8.08 (s, 1H),7.89-7.87 (d, 1H), 7.64-7.61 (dd, 1H), 7.47-7.45 (d, 1H), 7.44-7.41 (dd,1H), 7.40-7.38 (d, 1H), 7.34 (s, 1H), 7.19-7.18 (d, 1H), 6.40 (s, 1H),5.80-5.70 (m, 1H), 5.23 (s, 2H), 3.53 (s, 3H), 3.27-3.25 (m, 2H), 3.22(s, 3H), 2.50 (s, 3H), 2.40-2.30 (m, 2H), 2.23 (s, 3H)

Compound 154:

MS m/z (ESI): 664.5 [M+1]

Chiral HPLC analysis: retention time 8.579 min, (chromatographic column:CHIRAL PAK IE, 4.6*150 mm, 5 m; flow rate: 1 mL/min; mobile phase:methanol/ethanol=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.39 (s, 1H), 8.08 (s, 1H),7.89-7.87 (d, 1H), 7.64-7.61 (dd, 1H), 7.47-7.457 (d, 1H), 7.44-7.41(dd, 1H), 7.40-7.38 (d, 1H), 7.34 (s, 1H), 7.19-7.18 (d, 1H), 6.40 (s,1H), 5.80-5.70 (m, 1H), 5.23 (s, 2H), 3.53 (s, 3H), 3.27-3.25 (m, 2H),3.22 (s, 3H), 2.50 (s, 3H), 2.40-2.30 (m, 2H), 2.23 (s, 3H)

Example 1554-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)hexanamido)benzoicacid 155

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with butyl trifluoromethanesulfonate (preparedby a known method disclosed in “Perkin 1, 2000, (4), 571-574”),accordingly, the title compound 155 (25 mg) was prepared.

MS m/z (ESI): 511.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, 2H), 7.88 (d, 1H), 7.75 (d, 2H), 7.58(dd, 1H), 7.41 (d, 1H), 7.38 (s, 1H), 6.53 (s, 1H), 5.80-5.76 (m, 1H),3.65 (s, 3H), 2.55 (s, 3H), 2.28-2.14 (m, 2H), 1.50-1.37 (m, 4H), 0.98(t, 3H).

Example 1564-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propanamido)benzoicacid 156

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with iodomethane, accordingly, the titlecompound 156 (30 mg) was prepared.

MS m/z (ESI): 469.1 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.13 (d, 2H), 7.90 (d, 2H),7.73 (d, 1H), 7.53-7.50 (m, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 6.71 (s,1H), 6.11-6.06 (m, 1H), 3.65 (s, 3H), 2.55 (s, 3H), 1.77-1.75 (m, 3H).

Example 1574-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoicacid 157

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with iodoethane, accordingly, the titlecompound 157 (6 mg) was prepared.

MS m/z (ESI): 483.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 8.15 (d, 2H), 7.93 (d, 2H),7.73 (d, 1H), 7.53-7.50 (m, 1H), 7.34-7.29 (m, 2H), 6.72 (s, 1H),5.93-5.89 (m, 1H), 3.65 (s, 3H), 2.54 (s, 3H), 2.39-2.30 (m, 1H),2.08-2.03 (m, 1H), 1.12-1.08 (m, 3H).

Example 1584-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methylcyclopropyl)propanamido)benzoicacid 158

Step 1 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methylpent-4-enoate 158a

Compound 7b (250 mg, 638.01 μmol) was dissolved in 10 mL oftetrahydrofuran. After cooling to −78° C., the reaction solution wasadded with 3-bromo-2-methylpropene (172.26 mg, 1.28 mmol) and a solutionof lithium bis(trimethylsilyl)amide (427.02 mg, 2.55 mmol) intetrahydrofuran and stirred for 1 hour at −78° C. The reaction solutionwas added with saturated ammonium chloride solution to quench thereaction, and extracted with ethyl acetate. The organic phase wasconcentrated under reduced pressure and purified by silica gel columnchromatography with elution system B to obtain the title compound 158a(250 mg, yield: 87.87%).

Step 2 tert-butyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(1-methylcyclopropyl)propanoate 158b

In an ice bath, diethyl zinc (2.69 mmol, 2.69 mL) was dissolved in 15 mLof dichloromethane, and then a solution of trifluoroacetic acid (306.82mg, 2.69 mmol) in dichloromethane was slowly added dropwise, followed bydropwise addition of a solution of diiodomethane (720.72 mg, 2.69 mmol)in dichloromethane and a final solution of the pre-prepared compound158a (60 mg, 134.55 μmol) in dichloromethane. After stirring for 24hours at room temperature, the reaction solution was cooled in an icebath, added with 10 mL of hydrochloric acid, and extracted with ethylacetate (50 mL×3). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to obtain the crude title compound 158b (50 mg),which was directly used in the next reaction step without purification.

In accordance with the synthetic route of Example 7, the startingcompound 7d was replaced with crude compound 158b, accordingly, thetitle compound 158 (10 mg) was prepared.

MS m/z (ESI): 523.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 10.52 (s, 1H), 8.01-8.00 (m, 1H), 7.98-7.97(m, 1H), 7.87-7.85 (d, 1H), 7.77-7.76 (d, 1H), 7.75-7.74 (d, 1H),7.59-7.56 (dd, 1H), 7.40 (s, 1H), 7.39-7.38 (d, 1H), 6.51 (s, 1H),6.01-5.95 (m, 1H), 3.60 (s, 3H), 2.50 (s, 3H), 2.35-2.25 (m, 1H),2.00-1.90 (m, 1H), 1.18 (s, 3H), 0.42-0.38 (m, 1H), 0.35-0.31 (m, 1H),0.30-0.25 (m, 2H).

Example 1594-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoicacid 159

3-Cyclobutylpropionic acid 159a (500 mg, 3.90 mmol, prepared by a knownmethod disclosed in “Organic Process Research & Development, 2008, 12(2), 183-191”) was dissolved in 5 mL of carbon tetrachloride, and thenphosphorus tribromide (1.06 g, 3.90 mmol) and bromine (1.56 g, 9.75mmol) were added. The reaction solution was was heated to 85° C. andstirred for 12 hours. The reaction solution was cooled to roomtemperature and washed with saturated sodium bisulfate solution. Theorganic phase was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and purified by silicagel column chromatography with elution system B to obtain the titlecompound 159b (300 mg, yield: 37.14%).

In accordance with synthetic route in Example 30, the starting compound4a was replaced with compound 159b, accordingly, the title compound 159(60 mg) was prepared.

MS m/z (ESI): 541.1 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.74 (br, 1H), 10.82 (s, 1H), 7.93-7.90 (m,2H), 7.85-7.75 (m, 4H), 7.42 (d, 1H), 6.41 (d, 1H), 5.72-5.66 (m, 1H),3.65 (d, 3H), 2.49 (s, 3H), 2.27-2.18 (m, 3H), 2.01-1.91 (m, 2H),1.79-1.66 (m, 4H).

Examples 160, 161(R)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoicacid 160(S)-4-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoicacid 161

Compound 159 (50 mg, 92.43 μmol) was separated chirally (separationconditions: chromatographic column: Superchiral S-AD (Chiralway), 0.46cm ID*15 cm Length, 5 m; mobile phase: carbondioxide:ethanol:diethylamine=60:40:0.05, flow rate: 50 g/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 160 (20 mg) and compound 161 (20mg).

Compound 160:

MS m/z (ESI): 541.2 [M+1]

Chiral HPLC analysis: retention time 6.264 minutes, (chromatographiccolumn: Lux Amylose-1 (AD) 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=70/30(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, 2H), 7.73-7.63 (m, 4H), 7.46 (d, 1H),6.47 (s, 1H), 5.76-5.70 (m, 1H), 3.65 (d, 3H), 2.34 (d, 3H), 2.29-2.21(m, 3H), 2.06-1.43 (m, 6H).

Compound 161:

MS m/z (ESI): 541.4 [M+1]

Chiral HPLC analysis: retention time 9.045 minutes, (chromatographiccolumn: Lux Amylose-1 (AD) 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=70/30(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, 2H), 7.73-7.63 (m, 4H), 7.46 (d, 1H),6.47 (s, 1H), 5.76-5.70 (m, 1H), 3.65 (d, 3H), 2.34 (d, 3H), 2.29-2.21(m, 3H), 2.06-1.43 (m, 6H).

Example 1624-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-cyclobutoxybutanamido)benzoicacid 162

2-(Cyclobutoxy)ethanol 162a (224 mg, 1.93 mmol, prepared by a methoddisclosed in the patent application “WO 2015120786”) was dissolved in 10mL of dichloromethane, and then 2,6-dimethyl pyridine (206.64 mg, 1.93mmol) was added, followed by dropwise addition oftrifluoromethanesulfonic anhydride (598.49 mg, 2.12 mmol). Afterstirring for 2 hours, the reaction solution was added with 15 mL ofwater, and two phases were separated. The water phase was extracted with15 mL of dichloromethane. The organic phases were combined, washed withsaturated sodium chloride solution (15 mL×2), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure to obtain the crude title compound 162b (420 mg), whichwas directly used in the next reaction step without purification.

In accordance with synthetic route in Example 7, the starting compound7c was replaced with the crude compound 162b, accordingly, the titlecompound 162 (35 mg) was prepared.

MS m/z (ESI): 553.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ10.75 (s, 1H), 7.91-7.87 (m, 3H), 7.76 (d,2H), 7.63 (dd, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 6.42 (s, 1H), 5.79-5.75(m, 1H), 3.87-3.80 (m, 1H), 3.54 (s, 3H), 3.33-3.31 (m, 1H), 3.24-3.22(m, 1H), 2.49 (s, 3H), 2.41-2.28 (m, 2H), 2.10-2.01 (m, 2H), 1.82-1.68(m, 2H), 1.60-1.52 (m, 1H), 1.44-1.34 (m, 1H).

Examples 163, 164(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-cyclobutoxybutanamido)benzoic acid 163(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-cyclobutoxybutanamido)benzoicacid 164

Compound 162 (32 mg, 57.87 μmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IF, 20*250 mm, 5 μm;mobile phase: n-hexane:ethanol (containing 0.01% trifluoroaceticacid)=50:50, flow rate: 6.0 mL/min). The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompound 163 (15 mg) and compound 164 (15 mg).

Compound 163:

MS m/z (ESI): 553.4 [M+1]

Chiral HPLC analysis: retention time 3.577 minutes, (chromatographiccolumn: CHIRALPAK IF 150*4.6 mm, 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 7.91-7.87 (m, 3H), 7.77 (d,2H), 7.63 (dd, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 6.42 (s, 1H), 5.79-5.75(m, 1H), 3.87-3.80 (m, 1H), 3.54 (s, 3H), 3.33-3.31 (m, 1H), 3.24-3.16(m, 1H), 2.49 (s, 3H), 2.38-2.30 (m, 2H), 2.10-2.02 (m, 2H), 1.79-1.71(m, 2H), 1.59-1.50 (m, 1H), 1.44-1.36 (m, 1H).

Compound 164:

MS m/z (ESI): 553.4 [M+1]

Chiral HPLC analysis: retention time 8.134 minutes, (chromatographiccolumn: CHIRALPAK IF 150*4.6 mm, 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.79 (s, 1H), 7.91-7.87 (m,3H), 7.77 (d, 2H), 7.63 (dd, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 6.42 (s,1H), 5.78-5.75 (m, 1H), 3.87-3.80 (m, 1H), 3.54 (s, 3H), 3.33-3.31 (m,1H), 3.24-3.18 (m, 1H), 2.49 (s, 3H), 2.40-2.28 (m, 2H), 2.10-2.01 (m,2H), 1.81-1.68 (m, 2H), 1.59-1.52 (m, 1H), 1.46-1.36 (m, 1H).

Example 1654-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1R,4R)-4-hydroxycyclohexyl)propanamido)benzoicacid 165

Step 1 ethyl3-((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)acrylate 165b

(1R,4R)-4-((tert-Butyldimethylsilyl)oxy)cyclohexane-1-carbaldehyde 165a(3.2 g, 13.2 mmol, prepared by a known method disclosed in “Bioorganic &Medicinal Chemistry Letters, 2016 26(14), 3213-3215”) was dissolved in50 mL of toluene, and then (carbethoxymethylene)triphenylphosphorane(5.518 g, 15.84 mmol) was added. The reaction solution was warmed up to100° C. and stirred for 16 hours. The reaction solution was cooled toroom temperature, and concentrated under reduced pressure. The resultingresidue was added with 50 mL of saturated sodium bicarbonate solution,and extracted with ethyl acetate (100 mL×2). The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 165b (3.2 g, yield: 73.69%)

Step 2 ethyl3-((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)propanoate 165c

Compound 165b (1.5 g, 4.8 mmol) was dissolved in 30 mL of ethyl acetate,and then palladium on carbon (51.08 mg, 0.48 mmol) was added. Thereaction system was purged with hydrogen three times. The reactionsolution was stirred for 3 hours at room temperature, and then filtered.The filtrate was concentrated under reduced pressure and purified bysilica gel column chromatography with elution system B to obtain thetitle compound 165c (1.509 g, yield: 94.96%).

Step 32-bromo-3-((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)propanoate165d

Compound 165c (1.11 g, 3.53 mmol) was dissolved in 40 mL oftetrahydrofuran The reaction solution was cooled to −78° C., added withlithium bis(trimethylsilyl)amide (620.03 mg, 3.71 mmol) in batches, andstirred for 60 min, followed by addition of trimethylchlorosilane(383.39 mg, 3.53 mmol) and N-bromosuccinimide (628.08 mg, 3.53 mmol).After stirring for 2 hours, the reaction solution was warmed up to roomtemperature and then stirred for 1 hour. The reaction solution was addedwith 50 mL of saturated sodium chloride solution, and extracted withethyl acetate (50 mL×3). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and purified by silica gel column chromatographywith elution system B to obtain the title compound 165d (260 mg, yield:17.79%).

Step 42-bromo-3-((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)propanoicacid 165e

Compound 165d (260 mg, 0.66 mmol) was dissolved in 4 mL oftetrahydrofuran, and then lithium hydroxide monohydrate (83.19 mg, 1.98mmol) was added. After stirring for 2 hours, the reaction solution wasadded dropwise with 10% citric acid solution to adjust the pH to 3 to 4,and extracted with ethyl acetate (25 mL×2). The organic phases werecombined, washed with 50 mL of saturated sodium chloride solution, driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to obtain the crude title compound165e (240 mg), which was directly used in the next reaction step withoutpurification.

Step 5 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)propionicacid 165f

Magnesium tert-butoxide (171.41 mg, 1.01 mmol) was dissolved in 30 mL oftetrahydrofuran, and then the crude compound 165e (239.46 mg, 0.66mmol), potassium tert-butoxide (59.4 mg, 0.53 mmol) and compound 1f (140mg, 0.5 mmol) were added. After stirring for 16 hours at 60° C., thereaction solution was cooled to room temperature, added dropwise with 1M hydrochloric acid to adjust the pH to 3-4, and extracted with ethylacetate (100 mL×2). The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure and purified by silica gel column chromatographwith elution system A to obtain the title compound 165f (283 mg, yield:24.96%).

Step 6 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)propanamido)benzoate165g

Compound 165f (300 mg, 0.53 mmol) was dissolved in 20 mL of ethylacetate. The reaction solution was added with compound 4c (80.67 mg,0.53 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol), and then asolution of4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in ethylacetate (50%, 679.18 mg, 1.07 mmol). The reaction solution was warmed upto 60° C., and stirred for 2 hours. The reaction solution was cooled toroom temperature and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 165g (60 mg, yield: 15.36%).

Step 7 methyl4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1R,4R)-4-hydroxycyclohexyl)propanamido)benzoate165h

Compound 165g (60 mg, 0.09 mmol) was dissolved in 10 mL oftetrahydrofuran, and then tetrabutylammonium fluoride (180.49 mg, 0.69mmol) was added. The reaction solution was warmed up to 66° C. andstirred for 8 hours. After cooling to room temperature, the reactionsolution was added with 20 mL of water, and extracted with ethyl acetate(25 mL×4). The organic phases were combined, washed with water (25 mL×4)and saturated sodium chloride (25 mL) successively, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography with elution system A to obtain the title compound165h (26 mg, yield: 49.78%).

Step 84-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-((1R,4R)-4-hydroxycyclohexyl)propanamido)benzoicacid 165

Compound 165h (25 mg, 0.04 mmol) was dissolved in 3.63 mL of a mixedsolvent of tetrahydrofuran and methanol (V/V=10:1), and then 0.33 mL of1 M lithium hydroxide solution was added. After stirring for 16 hours,the reaction solution was dropwise added with 10% hydrochloric acid toadjust the pH to 3-4, and extracted with ethyl acetate (50 mL×2). Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by high performance liquid chromatography(Waters 2767-SQ detecor2, elution system: acetonitrile, water) to obtainthe title compound 165 (8 mg, yield: 32.46%).

MS m/z (ESI): 567.5 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 7.91-7.87 (m, 3H), 7.75 (s,1H), 7.73 (s, 1H), 7.64-7.62 (dd, 1H), 7.48-7.47 (d, 1H), 7.28 (s, 1H),6.42 (s, 1H), 5.95-5.83 (m, 1H), 4.46 (m, 1H), 3.54 (s, 3H), 2.48 (s,3H), 2.09-2.07 (m, 1H), 2.01-1.99 (m, 1H), 1.90-1.84 (m, 1H), 1.82-1.72(m, 4H), 1.08-0.96 (m, 4H).

Example 1664-(2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran)-2-yl)propanamido)benzoicacid 166

In accordance with the synthetic route of Example 8, the compound 8g wasreplaced with (tetrahydro-2H-pyran-2-yl)methyl trifluoromethanesulfonate(prepared by a method disclosed in the patent application“WO2016046159”), accordingly, the title compound 166 (30 mg) wasprepared.

MS m/z (ESI): 567.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.01-7.97 (m, 2H), 7.86-7.82 (m, 1H),7.75-7.70 (m, 2H), 7.58-7.55 (m, 1H), 7.41-7.38 (dd, 1H), 7.36-7.30 (m,1H), 6.49-6.48 (d, 1H), 5.91-5.60 (m, 1H), 4.00-3.94 (m, 1H), 3.62 (s,3H), 3.44-3.39 (m, 1H), 3.25-3.21 (m, 1H), 3.00-2.95 (m, 2H), 2.50-2.27(m, 2H), 1.85-1.74 (m, 1H), 1.71-1.68 (m, 1H), 1.66-1.45 (m, 3H),1.42-1.38 (m, 1H), 1.13-1.08 (m, 3H)

Example 1674-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanamido)benzoicacid 167

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with bromomethylcyclopropane (prepared by amethod disclosed in the patent application “CN106242941”), accordingly,the title compound 167 (18 mg) was prepared.

MS m/z (ESI): 509.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.93-7.88 (m, 3H), 7.76 (s,1H), 7.74 (s, 1H), 7.64-7.62 (d, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 6.42(s, 1H), 5.81-5.77 (m, 1H), 3.55 (s, 3H), 2.50 (s, 3H), 2.22-2.14 (m,1H), 1.91-1.83 (m, 1H), 0.68-0.64 (m, 1H), 0.49-0.42 (m, 1H), 0.40-0.33(m, 1H), 0.30-0.20 (m, 2H).

Example 168(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanamido)benzoic acid 168

Compound 167 (180 mg, 353.77 μmol) was separated chirally (separationconditions: chiral preparative column: Lux Amylose-1 (AD) 21.2*250 mm 5μm; mobile phase: n-hexane:ethanol (containing 0.01% trifluoroaceticacid)=30:70, flow rate: 10.0 mL/min). The corresponding fractions werecollected and concentrated under reduced pressure to obtain the titlecompound 168 (40 mg).

MS m/z (ESI): 509.4 [M+1]

Chiral HPLC analysis: retention time 11.482 minutes, (chromatographiccolumn: Lux Amylose-1 (AD) 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=70/30(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.01-8.00 (m, 1H), 7.98-7.97 (m, 1H),7.90-7.85 (d, 1H), 7.75-7.74 (m, 1H), 7.73-7.71 (m, 1H), 7.59-7.56 (dd,1H), 7.40 (s, 1H), 7.39-7.38 (d, 1H), 6.51 (s, 1H), 5.84-5.80 (m, 1H),3.60 (s, 3H), 2.50 (s, 3H), 2.20-2.00 (m, 2H), 0.85-0.75 (m, 1H),0.55-0.45 (m, 2H), 0.35-0.25 (m, 2H)

Example 1694-(2-(4-(6-acetyl-3-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanamido)benzoicacid 169

In accordance with the synthetic route of Example 30, the startingcompound 4a was replaced with (bromomethyl)cyclopropane to obtain thetitle compound 169 (20 mg).

MS m/z (ESI): 527.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.01-8.00 (d, 1H), 7.99-7.98 (d, 1H),7.76-7.67 (m, 4H), 7.49-7.46 (d, 1H), 6.48 (s, 1H), 5.90-5.80 (m, 1H),3.66 (s, 3H), 2.53-2.48 (m, 3H), 2.15-2.05 (m, 2H), 0.80-0.75 (m, 1H),0.55-0.45 (m, 2H), 0.25-0.20 (m, 2H)

Example 1704-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoicacid 170

In accordance with the synthetic route of Example 4, the startingcompound 4a was replaced with compound 159b, accordingly, the titlecompound 170 (42 mg) was prepared.

MS m/z (ESI): 523.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.00 (m, 2H), 7.89 (d, 1H), 7.77-7.74 (m,2H), 7.59 (dd, 1H), 7.41 (d, 1H), 7.38 (s, 1H), 6.51 (s, 1H), 5.76-5.72(m, 1H), 3.66 (s, 3H), 2.56 (s, 3H), 2.36-2.23 (m, 3H), 2.20-2.10 (m,2H), 1.96-1.77 (m, 4H).

Examples 171, 172(S)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoicacid 171(R)-4-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-cyclobutylpropanamido)benzoicacid 172

Compound 170 (38 mg, 0.07 mmol) was separated chirally (separationconditions: chiral preparative column CHIRAL PAK IE, 20*250 mm, 5 m;mobile phase: ethanol (containing 0.01% trifluoroacetic acid)=100, flowrate: 6.0 mL/min). The corresponding fractions were collected andconcentrated under reduced pressure to obtain the title compound 171 (18mg) and compound 172 (18 mg).

Compound 171:

MS m/z (ESI): 523.2 [M+1]

Chiral HPLC analysis: retention time 9.644 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=40/60(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.00 (m, 2H), 7.89 (d, 1H), 7.77-7.74 (m,2H), 7.59 (dd, 1H), 7.41 (d, 1H), 7.38 (s, 1H), 6.51 (s, 1H), 5.76-5.72(m, 1H), 3.66 (s, 3H), 2.56 (s, 3H), 2.36-2.23 (m, 3H), 2.20-2.10 (m,2H), 1.96-1.77 (m, 4H).

Compound 172:

MS m/z (ESI): 523.2 [M+1]

Chiral HPLC analysis: retention time 3.831 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=40/60(v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.00 (m, 2H), 7.89 (d, 1H), 7.77-7.74 (m,2H), 7.59 (dd, 1H), 7.41 (d, 1H), 7.38 (s, 1H), 6.51 (s, 1H), 5.76-5.72(m, 1H), 3.66 (s, 3H), 2.56 (s, 3H), 2.36-2.23 (m, 3H), 2.20-2.10 (m,2H), 1.96-1.77 (m, 4H).

Example 1734-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(3,3-dimethylcyclobutyl)propanamido)benzoicacid 173

In accordance with the synthetic route of Example 165, the startingcompound 165a was replaced with 3,3-dimethylcyclobutane-1-carbaldehyde(prepared by a method disclosed in the patent application“WO2015129926”), accordingly, the title compound 173 (25 mg) wasprepared.

MS m/z (ESI): 551.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H), 7.98 (s, 1H), 7.88-7.86 (d, 1H),7.74 (s, 1H), 7.72 (s, 1H), 7.59-7.26 (dd, 1H), 7.40-7.39 (d, 1H), 7.37(s, 1H), 6.49 (s, 1H), 5.71-5.69 (m, 1H), 3.64 (s, 3H), 2.53 (s, 3H),2.30-2.25 (m, 3H), 1.95-1.85 (m, 2H), 1.65-1.60 (m, 1H), 1.55-1.50 (m,1H), 1.26 (s, 3H), 1.06 (s, 3H).

Example 1744-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydrofuran-2-yl)propanamido)benzoic acid 174

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with (tetrahydrofuran-2-yl)methyltrifluoromethanesulfonate (prepared by a method disclosed in the patentapplication “WO2003095438”), accordingly, the title compound 174 (15 mg)was prepared.

MS m/z (ESI): 539.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.01-8.00 (m, 1H), 7.98-7.97 (m, 1H),7.90-7.85 (m, 1H), 7.75-7.71 (m, 2H), 7.59-7.56 (dt, 1H), 7.40-7.38 (m,1H), 7.37-7.34 (m, 1H), 6.52-6.48 (m, 1H), 5.70-5.60 (m, 1H), 3.95-3.85(m, 2H), 3.75-3.70 (m, 1H), 3.64 (s, 3H), 2.54 (s, 2H), 2.51 (s, 1H),2.50-2.22 (m, 2H), 2.16-2.10 (m, 1H), 2.00-1.95 (m, 2H), 1.65-1.60 (m,1H).

Example 1754-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-methoxycyclohexyl)propanamido)benzoicacid 175

In accordance with the synthetic route of Example 165, the startingcompound 165a was replaced with 4-methoxycyclohexane-1-carboxaldehyde(prepared by a method disclosed in the patent application“WO2016044626”), accordingly, the title compound 175 (8 mg) wasprepared.

MS m/z (ESI): 581.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.00-7.37 (m, 8H), 6.78-6.53 (m, 1H), 5.95 (s,1H), 3.89-3.82 (m, 1H), 3.66-3.62 (m, 3H), 3.48-3.16 (m, 3H), 2.68-2.54(m, 3H), 2.09-1.90 (m, 5H), 1.66-1.14 (m, 6H).

Example 1764-(2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran)-2-yl)propanamido)benzoicacid 176

In accordance with the synthetic route of Example 7, the startingcompound 7c was replaced with (tetrahydro-2H-pyran-2-yl)methyltrifluoromethanesulfonate, accordingly, the title compound 176 (15 mg)was prepared.

MS m/z (ESI): 553.4 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 7.92-7.87 (m, 3H), 7.79-7.75(m, 2H), 7.64-7.61 (dd, 1H), 7.47-7.45 (dd, 1H), 7.31-7.27 (d, 1H), 6.39(s, 1H), 5.72-5.65 (m, 1H), 3.90-3.85 (m, 1H), 3.54 (s, 3H), 3.31-3.08(m, 2H), 2.50 (s, 3H), 2.25-2.35 (m, 1H), 2.22-2.15 (m, 1H), 2.10-2.00(m, 1H), 1.80-1.70 (m, 1H), 1.65-1.55 (m, 1H), 1.50-1.35 (m, 3H).

Examples 177, 1784-[[(2S)-4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyryl]amino]benzoicacid 1774-[[(2R)-4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyryl]amino]benzoicacid 178

Step 1 2-methoxy-5-(trideuteromethoxy)pyridine 177b

6-Methoxypyridin-3-ol 177a (4.0 g, 31.97 mmol, prepared by a knownmethod disclosed in “Medicinal Chemistry Research, 2013, 22(4),1825-1836”) was dissolved in 50 mL of N,N-dimethylformamide, and thenpotassium carbonate (13.25 g, 95.90 mmol) was added.Trideuteroiodomethane (6.95 g, 47.95 mmol) was added dropwise in an icebath, and the internal temperature of the reaction solution wascontrolled to not exceed 20° C. during the dropwise addition. Thedropwise addition was completed within 1 hour, and the reaction solutionwas warmed up to room temperature and stirred for 3 hours. The reactionsolution was added with 100 mL of water, extracted with ethyl acetate(300 mLxl), separated, washed with water (100 mL×5) and saturated sodiumchloride solution (100 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to obtainthe crude title compound 177b (4.4 g), which was directly used in thenext reaction step without purification.

Step 2 [2-methoxy-5-(trideuteromethoxy)-4-pyridyl]boronic acid 177c

The crude compound 177b (4.40 g, 30.95 mmol) was dissolved in 50 mL oftetrahydrofuran. The reaction solution was cooled to −78° C., and 2M asolution of lithium diisopropylamide intetrahydrofuran/n-heptane/ethylbenzene (30.95 mL, 61.90 mmol) was addeddropwise. During the dropwise addition, the internal temperature of thereaction solution is controlled to not exceed −65° C. After completionof the addition, the reaction solution was stirred for 0.5 hour at −78°C., and then triisopropyl borate (6.63 g, 61.90 mmol) is slowly addeddropwise, and the internal temperature of the reaction solution wascontrolled not to exceed −65° C. during the dropwise addition. Aftercompletion of the addition, the reaction solution was stirred for 2hours at −78° C. The reaction solution was added with 80 mL of water toquench the reaction, added with ethyl acetate (80 mL), and two phaseswere separated. The water phase was added with 6M hydrochloric acid toadjust the pH to 3-4. A solid was precipitated, and the mixture wasfiltered. The filter cake was collected and naturally dried to obtainthe crude title compound 177c (2.5 g), which was directly used in thenext reaction step without purification.

Step 31-[4-chloro-2-[2-methoxy-5-(trideuteromethoxy)-4-pyridyl]phenyl]propan-1-one177d

Compound 8c (400 mg, 1.62 mmol) was dissolved in 13 mL of a mixedsolvent of 1,4-dioxane and water (V:V=10:3), and then the crude compound177c (300.57 mg, 1.62 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (59.94 mg,80.80 μmol) and sodium carbonate (513.91 mg, 4.85 mmol) were added. Thereaction solution was warmed up to 85° C., and stirred for 16 hours. Thereaction solution was naturally cooled to room temperature and filtered.The filtrate was added with 30 mL of water, and extracted with ethylacetate (80 mL×2). The organic phases were combined, washed withsaturated sodium chloride solution (50 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography with elution system B to obtain the title compound 177d(353 mg, yield: 70.74%).

Step 4 tert-butyl2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]acetate177e

Compound 177d (352 mg, 1.14 mmol) and compound 7a (667.08 mg, 3.42 mmol)were mixed, heated to 100° C., and stirred for 2 hours. The reactionsolution was cooled to room temperature. The resulting residue waspurified by silica gel column chromatography with elution system B toobtain the title compound 177e (252 mg, yield: 54.06%).

Step 5 tert-butyl4-tert-butoxy-2-[4-(5-chloro-2-propionylphenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyrate177f

Compound 177e (252 mg, 616.30 μmol) and compound 108b (462.66 mg, 1.85mmol) were dissolved in 15 mL of tetrahydrofuran, and the reactionsolution was cooled to −78° C., followed by dropwise addition of lithiumbis(trimethylsilyl)amide solution (2.47 mL, 2.47 mmol). After stirringfor 2 hours, the reaction solution was slowly added with 50 mL of waterto quench the reaction at −78° C. The reaction solution was warmed up toroom temperature, and extracted with ethyl acetate (60 mL×2). Theorganic phases were combined and washed with saturated sodium chloridesolution (50 mL), dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem B to obtain the title compound 177f (80 mg, yield: 25.5%).

Step 64-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyric acid 177 g

Compound 177f (80 mg, 157.16 μmol) was dissolved in a mixed solvent of 2mL of water, 2 mL of methanol and 10 mL of tetrahydrofuran, and thenlithium hydroxide monohydrate (33 mg, 785.78 μmol) was added. Afterstirring for 16 hours, the reaction solution was dropwise added with 1Mhydrochloric acid to adjust the pH to 3-4, and extracted with ethylacetate (50 mL×2). The organic phases were combined, washed withsaturated sodium chloride solution (30 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure to obtain the crude title compound 177g (60 mg), which wasdirectly used in the next reaction step without purification.

Step 74-[[4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyryl]amino]benzoicacid 177h

The crude compound 177g (60.09 mg, 132.66 μmol) was dissolved in 20 mLof tetrahydrofuran, and then N,N-diisopropylethylamine (68.58 mg, 530.63μmol) and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 168.74 mg, 265.31 μmol) were added successively.After stirring for 10 minutes, the reaction solution was added withcompound 8j (19.10 mg, 139.29 μmol), and stirred for 3 hours. Thereaction solution was added with 30 mL of water, and extracted withethyl acetate (50 mL×2). The organic phases were combined, and washedwith saturated sodium chloride solution (30 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and purified by high performance liquid chromatography(Waters 2767, elution system: acetonitrile, water, 0.05% trifluoroaceticacid) to obtain the title compound 177h (30 mg, yield: 39.53%).

MS m/z (ESI): 572.1 [M+1]

Step 84-[[(2S)-4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyryl]amino]benzoicacid 1774-[[(2R)-4-tert-butoxy-2-[4-(5-chloro-2-propionyl-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]butyryl]amino]benzoicacid 178

Compound 177h (30 mg, 52.44 μmol) was separated chirally (separationconditions: chiral preparative column: Daicel IE 20*250 mm 5 m; mobilephase: n-hexane/ethanol=50/50 (v/v), flow rate: 20 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 177 (8 mg) and compound 178 (8mg).

Compound 177:

MS m/z (ESI): 572.1 [M+1]

Chiral HPLC analysis: retention time 7.640 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 m; mobile phase: n-hexane/ethanol(containing 0.1% trifluoroacetic acid)=50/50 (v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.01 (m, 2H), 7.83-7.76 (m, 3H), 7.57 (s,1H), 7.36 (m, 2H), 6.52 (s, 1H), 5.88-5.87 (m, 1H), 3.55-3.45 (m, 2H),3.01-2.97 (m, 2H), 2.48-2.40 (m, 2H), 1.18-1.12 (m, 12H).

Compound 178:

MS m/z (ESI): 572.1 [M+1]

Chiral HPLC analysis: retention time 4.703 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 m; mobile phase: n-hexane/ethanol(containing 0.1% trifluoroacetic acid)=50/50 (v/v)).

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.01 (m, 2H), 7.83-7.76 (m, 3H), 7.57 (s,1H), 7.36 (m, 2H), 6.52 (s, 1H), 5.88-5.87 (m, 1H), 3.55-3.45 (m, 2H),3.01-2.97 (m, 2H), 2.48-2.40 (m, 2H), 1.18-1.12 (m, 12H).

Examples 179, 1804-[[(2S)-2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 1794-[[(2R)-2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 180

Step 1 to Step 54-[[2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 179e

In accordance with the synthetic route of compound 177h in Examples 177,178, the starting compound 8c was replaced with the compound 1c, and thecompound 108b was replaced with the compound 8g, accordingly, the titlecompound 179e (200 mg) was prepared.

Step 64-[[(2S)-2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 1794-[[(2R)-2-[4-(2-acetyl-5-chloro-phenyl)-2-oxo-5-(trideuteromethoxy)-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 180

Compound 179e (200 mg, 364.96 μmol) was separated chirally (separationconditions: chiral preparative column: Daicel IE 20*250 mm 5 μm; mobilephase: n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50(v/v), flow rate: 20 mL/min). The corresponding fractions were collectedand concentrated under reduced pressure to obtain the title compound 179(35 mg) and compound 180 (35 mg).

Compound 179:

MS m/z (ESI): 548.0 [M+1]

Chiral HPLC analysis: retention time 13.346 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm; mobile phase: n-hexane/ethanol(containing 0.1% trifluoroacetic acid)=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H), 7.93 (d, 2H), 7.83 (d, 1H),7.76 (d, 2H), 7.61 (d, 1H), 7.39 (d, 2H), 7.26-7.30 (m, 4H), 7.18-7.22(m, 1H), 6.32 (s, 1H), 6.02-6.06 (m, 1H), 3.47-3.50 (m, 2H), 2.38 (s,3H).

Compound 180:

MS m/z (ESI): 548.0 [M+1]

Chiral HPLC analysis: retention time 4.909 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm; mobile phase: n-hexane/ethanol(containing 0.1% trifluoroacetic acid)=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H), 7.93 (d, 2H), 7.83 (d, 1H),7.76 (d, 2H), 7.61 (d, 1H), 7.39 (d, 2H), 7.26-7.30 (m, 4H), 7.18-7.22(m, 1H), 6.32 (s, 1H), 6.02-6.06 (m, 1H), 3.47-3.50 (m, 2H), 2.38 (s,3H).

Examples 181, 1824-[[(2S)-2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino]benzoicacid 1814-[[(2R)-2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino]benzoicacid 182

Step 1 ethyl2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2)-yl)acetate181b

Compound 1e (20.3 g, 69.59 mmol) and ethyl 2-bromoacetate 181a (34.86 g,208.76 mmol, prepared by a known method disclosed in “Euroean Journal ofOrganic Chemistry, 2002, (17), 3015-3023”) were mixed. The reactionsolution was warmed up to 100° C. and stirred for 3 hours. After coolingto room temperature, the reaction solution was added with 50 mL ofisopropanol, stirred for 16 hours to precipitate a large amount ofsolid, and filtered. The filter cake was washed with isopropanol (10mL×2) and n-hexane (10 mL×2) successively. The filter cake was collectedand dried in vacuo to obtain the crude title compound 181b (18.5 g),which was directly used in the next reaction step without purification.

Step 2 ethyl2-[4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionate181d

The crude compound 181b (18.5 g, 50.85 mmol) was dissolved indichloromethane (250 mL), and then1-[bromo(dideutero)methyl]-2,3,4,5,6-pentadeutero-benzene 181e (22.64 g,127.13 mmol, prepared by a known method disclosed in “AngewandteChemie-International Edition, 2015, 54 (18), 5478-5482”) was added.Under an argon atmosphere, the reaction solution was cooled to −78° C.,added dropwise with lithium bis(trimethylsilyl)amide solution (25.27 mL,254.27 mmol), and stirred for 2 hours. The low temperature bath wasremoved, and the reaction solution was slowly added dropwise with 100 mLof saturated ammonium chloride solution to quench the reaction. Thereaction solution was naturally warmed up to room temperature, addedwith 30 m of water, and two phases were separated. The water phase wasextracted with ethyl acetate (100 mL×3). The organic phases werecombined, washed with saturated sodium chloride solution (100 mL), driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to obtain the crude title compound181d (30 g), which was directly used in the next reaction step withoutpurification.

Step 32-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionicacid 181e

The crude compound 181d (23.44 g, 50.85 mmol) was dissolved in 100 mL ofTHF, and then 1M sodium hydroxide solution (71.19 mL, 71.19 mmol) wasadded. After stirring for 16 hours, the reaction solution wasconcentrated under reduced pressure to remove tetrahydrofuran, and theresulting residue was extracted with methyl tert-butyl ether (100 mL×3).The water phase was added with concentrated hydrochloric acid to adjustthe pH to 2-3, and extracted with ethyl acetate (100 mL×3). The organicphases were combined, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography with elutionsystem C to obtain the title compound 181e (11.7 g, yield: 53.15%).

Step 44-[[2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino]benzoicacid 181f

Compound 181e (11.7 g, 27.03 mmol) was dissolved in 60 mL oftetrahydrofuran, and then a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 25.8 g, 40.54 mmol) was added in an ice bath. Thereaction solution was stirred well, added with N,N-diisopropylethylamine(10.48 g, 81.08 mmol), stirred for 10 minutes in an ice bath, and addedwith compound 8j (3.71 g, 27.03 mmol) in batches. The reaction solutionwas warmed up to room temperature and stirred for 0.5 hour. The reactionsolution was added with 100 mL of water to quench the reaction, stirredfor 10 minutes, and two phases were separated. The water phase wasextracted with ethyl acetate (50 mL×3). The organic phases werecombined, concentrated under reduced pressure to remove the organicsolvent, added with 200 mL of ethyl acetate, washed with saturatedsodium chloride solution (50 mL), and concentrated under reducedpressure. The resulting residue was added to 100 mL of isopropanol,warmed up to 90° C. and stirred for 20 minutes, cooled to roomtemperature and stirred for 16 hours, and filtered. The filter cake waswashed with isopropanol (20 mL×2) and methyl tert-butyl ether (20 mL×2)successively, and the filter cake was collected to obtain the crudetitle compound 181f (13.4 g), which was directly used in the nextreaction step without purification.

Step 54-[[(2S)-2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino]benzoicacid 1814-[[(2R)-2-[4-(2-acetyl-5-chloro-phenyl)-5-methoxy-2-oxo-1-pyridyl]-3,3-dideutero-3-(2,3,4,5,6-pentadeuterophenyl)propionyl]amino]benzoicacid 182

Compound 181f (13.4 g, 24.27 mmol) was separated chirally (separationconditions: chiral preparative column: CHIRAL PAK AD 5.0*250 mm; mobilephase: carbon dioxide/(70% ethanol/30% acetonitrile/0.1%diethylamine)=60/40 (v/v), flow rate: 59 mL/min). The correspondingfractions were collected, and concentrated under reduced pressure. Theresulting residue was dissolved in 100 mL of dichloromethane, dropwiseadded with 50 mL of 0.5 Mhydrochloric acid in an ice bath, stirred for15 minutes at room temperature, and extracted with dichloromethane (30mL×2). The organic phases were combined, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The resulting residue was added to 100 mL of methanol andstirred for 1 hour, and filtered. The filter cake was collected, washedwith methanol (10 mL) and methyl tert-butyl ether (10 mL×2)successively, and dried in vacuum to obtain the title compound 181 (5.5g) and compound 182 (4.8 g).

Compound 181:

MS m/z (ESI): 552.6 [M+1]

Chiral HPLC analysis: retention time 12.738 min, chiral purity 99.8%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 m; mobile phase:n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.83 (s, 1H), 7.92 (d, 2H),7.82 (d, 1H), 7.76 (d, 2H), 7.60 (d, 1H), 7.42 (s, 1H), 7.37 (s, 1H),6.30 (s, 1H), 6.01 (s, 1H), 3.54 (s, 3H), 2.37 (s, 3H).

Compound 182:

MS m/z (ESI): 552.6 [M+1]

Chiral HPLC analysis: retention time 4.902 minutes, chiral purity 99.1%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 m; mobile phase:n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50 (v/v))).

¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.83 (s, 1H), 7.92 (d, 2H),7.82 (d, 1H), 7.76 (d, 2H), 7.60 (d, 1H), 7.42 (s, 1H), 7.37 (s, 1H),6.30 (s, 1H), 6.01 (s, 1H), 3.54 (s, 3H), 2.37 (s, 3H).

Examples 183, 1844-[[(2S)-2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 1834-[[(2R)-2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 184

Step 1 1-(2-bromo-4-chloro-phenyl)-2,2,2-trideutero-ethanone 183b

Compound 8a (3.8 g, 11.97 mmol) was dissolved in 50 mL oftetrahydrofuran. The reaction solution was cooled to −10° C., slowlydropwise added with isopropylmagnesium chloride (1.6 g, 15.57 mmol), andpre-reacted for 0.5 hour. 2,2,2-Trideuteroacetyl chloride 183a (1.27 g,15.57 mmol), lithium chloride (21.70 mg, 359.23 μmol), cuprous chloride(35.56 mg, 359.23 μmol) and aluminum trichloride (47.90 mg, 359.23 μmol)were added to 50 mL of tetrahydrofuran, and the mixture was uniformlystirred at room temperature. The reaction solution which had beenpre-reacted for 0.5 hour was added to the above mixture, and reacted for0.5 hour at room temperature. The reaction solution was washed with 50mL of 3M hydrochloric acid, and the water phase was extracted with ethylacetate (100 mL). The organic phase was washed with saturated sodiumchloride solution (60 mL), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to obtainthe crude title compound 183b (2.5 g), which was directly used in thenext reaction step without purification.

Step 2

1-[4-chloro-2-(2,5-dimethoxy-4-pyridyl)phenyl]-2,2,2-trideutero-ethanone183c Compound 183b (400 mg, 1.69 mmol) and compound 1d (309.45 mg, 1.69mmol) were dissolved in a mixed solvent of 8 mL of 1,4-dioxane and 1 mLof deuteroxide, and then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (61.88 mg,84.56 μmol) and sodium carbonate (537.83 mg, 5.07 mmol) were added. Thereaction solution was heated to 85° C., and stirred for 5 hours. Thereaction solution was naturally cooled to room temperature, added with30 mL of water, and extracted with ethyl acetate (50 mL×2). The organicphases were combined, washed with water (40 mL) and saturated sodiumchloride solution (40 mL) successively, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography with elution system B to obtain the title compound 183c(400 mg, yield: 80.24%).

MS m/z (ESI): 295.4 [M+1]

Step 3 tert-butyl2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]acetate183d

Compound 183c (400 mg, 1.36 mmol) and compound 7a (794.12 mg, 4.07 mmol)were mixed, warmed up to 100° C. and stirred for 2 hours. The reactionsolution was cooled to room temperature. The resulting residue waspurified by silica gel column chromatography with elution system B toobtain the title compound 183d (480 mg, yield: 89.57%).

Step 4 tert-butyl2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionate183e

Compound 183d (480 mg, 1.22 mmol) was dissolved in 20 mL oftetrahydrofuran. After cooling to −78° C., the reaction solution wasadded with compound 8g (623.73 mg, 3.65 mmol), dropwise added with asolution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (4.86mL, 4.86 mmol), and stirred at −78° C. for 1.5 hours. The reactionsolution was added with 4.0 mL of deuteroxide to quench the reaction,warmed up to room temperature, and extracted with ethyl acetate (50mL×2). The organic phases were combined, washed with saturated sodiumchloride solution (20 mL×2), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel column with elution systemA to obtain the title compound 183e (494 mg, yield: 83.79%).

Step 52-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenylpropionicacid 183f

Compound 183e (494 mg, 1.02 mmol) was dissolved in 10 mL ofdichloromethane, and then trifluoroacetic acid (2.3 g, 20.33 mmol) wasadded dropwise. After stirring for 2 hours, the reaction solution wasconcentrated under reduced pressure to obtain the crude title compound183f (430 mg), which was directly used in the next reaction step withoutpurification.

Step 64-[[2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridine]-3-phenyl-propionyl]amino]benzoicacid 183g

The crude compound 183f (430 mg, 990.95 μmol) was dissolved in 10 mL oftetrahydrofuran, and then N,N-diisopropylethylamine (512 mg, 3.96 mmol)and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 1.51 g, 1.98 mmol) were added in an ice bath. Afterstirring for 10 minutes in an ice bath, the reaction solution was addedwith compound 8j (136 mg, 991.72 μmol), warmed up to room temperatureand stirred for 2 hours. The reaction solution was added with 25 mL ofethyl acetate, washed with water (15 mL) and saturated sodium chloridesolution (15 mL) successively, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography withelution system A to obtain the title compound 183g (512 mg, yield:94.28%).

Step 74-[[(2S)-2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 1834-[[(2R)-2-[4-[5-chloro-2-(2,2,2-trideuteroacetyl)phenyl]-5-methoxy-2-oxo-1-pyridyl]-3-phenyl-propionyl]amino]benzoicacid 184

Compound 183g (512 mg, 934.31 μmol) was separated chirally (separationconditions: chiral preparative column Daicel IE 20*250 mm 5 μm; mobilephase: n-hexane:ethanol=60:40, flow rate: 20 mL/min). The correspondingfractions were collected and concentrated under reduced pressure toobtain the title compound 183 (200 mg) and compound 184 (200 mg).

Compound 183:

MS m/z (ESI): 548.0 [M+1]

Chiral HPLC analysis: retention time 12.947 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol (containing 0.1% trifluoroacetic acid)/n-hexane=50/50(v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (br, 1H), 10.85 (s, 1H), 7.93 (d, 2H),7.83 (d, 1H), 7.77 (d, 2H), 7.62 (d, 1H), 7.41 (d, 2H), 7.32-7.26 (m,4H), 7.22-7.18 (m, 1H), 6.32 (s, 1H), 6.06-6.02 (m, 1H), 3.55 (s, 3H),3.50-3.43 (m, 2H).

Compound 184:

MS m/z (ESI): 548.0 [M+1]

Chiral HPLC analysis: retention time 4.840 minutes, (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm (with a guard column); mobilephase: ethanol (containing 0.1% trifluoroacetic acid)/n-hexane=50/50(v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (br, 1H), 10.85 (s, 1H), 7.93 (d, 2H),7.83 (d, 1H), 7.77 (d, 2H), 7.62 (d, 1H), 7.41 (d, 2H), 7.32-7.26 (m,4H), 7.22-7.18 (m, 1H), 6.32 (s, 1H), 6.06-6.02 (m, 1H), 3.55 (s, 3H),3.50-3.43 (m, 2H).

Comparative Example 1 (Example 185)(S)-4-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(21)-yl)-3-(pyridin-4-yl)propanamido)benzoicacid

Step 1 4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile 185b

2-Bromo-4-chloro-benzonitrile 185a (5.92 g, 27.33 mmol, prepared by aknown method disclosed in “Angewandte Chemie, International Edition,2017, 56(9), 2473-2477”) was dissolved in 180 mL 1,4-dioxane, and thencompound 1d (5 g, 27.33 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.03 g,2.73 mmol) and potassium carbonate (11.33 g, 81.98 mmol) were added.Under an argon atmosphere, the reaction solution was warmed up to 110°C., and stirred for 16 hours. The reaction solution was naturally cooledto room temperature, and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn with elution system B to obtain the title compound 185b (6.5 g,yield: 86.59%).

Step 2 tert-butyl2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)acetate185c

Compound 185b (5 g, 18.20 mmol) and compound 7a (21.30 g, 109.21 mmol)were mixed. The reaction solution was heated to 100° C., and stirred for3 hours. The reaction solution was cooled to 90° C. and stirred for 4hours. The reaction solution was cooled to room temperature. Theresulting residue was purified by elution system B to obtain the titlecompound 185c (5 g, yield: 73.29%).

Step 3 tert-butyl2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-4-yl)propionate185e

Compound 185c (200 mg, 533.39 μmol) and 4-(bromomethyl)pyridinehydrobromide 185d (269.92 mg, 1.07 mmol, prepared by a known methoddisclosed in “Chemical Communications (Cambridge, United Kingdom), 2011,47 (5), 1482-1484”) were dissolved in 10 mL of tetrahydrofuran. Thereaction solution was cooled to −78° C., dropwise added with lithiumbis(trimethylsilyl)amide solution (3.2 mL, 3.2 mmol), and stirred for 2hours. At −78° C., the reaction solution was slowly added with 10 mL ofwater to quench the reaction, and then added with 10 mL of saturatedsodium chloride solution. The reaction solution was naturally warmed upto room temperature, and extracted with ethyl acetate (20 mL×3). Thephases were combined, washed with saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography with elution system A toobtain the title compound 185e (240 mg, yield: 96.53%).

Step 42-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-4-yl)propanoicacid 185f

Compound 185e (240 mg, 515.10 μmol) was dissolved in 6 mL ofdichloromethane, and then trifluoroacetic acid (1 mL, 515.1 μmol) wasadded. The reaction solution was stirred for 16 hours, and thenconcentrated under reduced pressure to obtain the title compound 185f(211.1 mg), which was directly used in the next reaction step withoutpurification.

Step 54-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(pyridin-4-yl)propanamido)benzoicacid 185g

The crude compound 185f (211 mg, 514.86 μmol) was dissolved in 10 mL ofethyl acetate, and then compound 8j (70.61 mg, 514.86 μmol),N,N-diisopropylethylamine (665.40 mg, 5.15 mmol) and a solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inethyl acetate (50%, 982.90 mg, 1.54 mmol) were added. The reactionsolution was warmed up to 68° C. and stirred for 1.5 hours. The reactionsolution was cooled to room temperature, and concentrated under reducedpressure. The resulting residue was added with 20 mL of water, addedwith 3M hydrochloric acid to adjust the pH to 5. A solid wasprecipitated, and the mixture was filtered. The filter cake wascollected and purified by silica gel column chromatography with elutionsystem A to obtain the title compound 185g (35 mg, yield: 12.85%).

Step 6(S)-4-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-(2H)-yl)-3-(pyridin-4-yl)propanamido)benzoicacid 185

Compound 185g (33 mg, 62.39 μmol) was separated chirally (separationconditions: chiral preparative column: CHIRAL PAK IG 2.5*250 mm; mobilephase: ethanol/acetic acid=100/0.1 (v/v), flow rate: 30 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 185 (14 mg).

MS m/z (ESI): 529.5 [M+1]

Chiral HPLC analysis: retention time 9.464 minutes, chiral purity 97.5%(chromatographic column: CHIRAL PAK IE 4.6*150 mm 5 μm; mobile phase:n-hexane/ethanol (containing 0.1% trifluoroacetic acid)=50/50 (v/v)).

¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.43-8.32 (m, 2H), 7.98-7.91(m, 3H), 7.70-7.55 (m, 5H), 7.27-7.16 (m, 2H), 6.41-6.38 (m, 1H),6.11-6.05 (m, 1H), 3.68-3.59 (m, 4H), 3.56-3.49 (m, 1H).

Comparative Example 2 (Example 186)(S)-4-(tert-butoxy)-2-(4-(5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(quinoxalin-6-yl)butanamide 186

Compound 186a (80 mg, 132.65 μmol, prepared by a method disclosed in thepatent application “WO2017005725”) was separated chirally (separationconditions: chiral preparative column: Daicel IE 20*250 mm, 5 μm; mobilephase: ethanol/n-hexane=40/60 (v/v), flow rate: 15 mL/min). Thecorresponding fractions were collected and concentrated under reducedpressure to obtain the title compound 186 (30 mg).

MS m/z (ESI): 603.2 [M+1]

Chiral HPLC analysis: retention time 9.362 minutes (chromatographiccolumn: CHIRAL PAK IE 4.6*150 mm 5 μm; mobile phase: n-hexane/ethanol(containing 0.1% trifluoroacetic acid)=30/70 (v/v)).

¹H NMR (400 MHz, CD₃OD) δ 10.80 (s, 1H), 8.85-8.83 (m, 1H), 8.80-8.79(m, 1H), 8.61-8.60 (m, 1H), 8.08-8.07 (m, 2H), 8.06 (s, 1H), 7.70-7.69(m, 1H), 7.68-7.65 (m, 1H), 7.57-7.50 (m, 1H), 6.61 (s, 1H), 6.00-5.90(m, 1H), 3.60-3.59 (m, 1H), 3.57-3.47 (s, 3H), 3.50-3.40 (m, 1H),2.53-2.52 (m, 1H), 2.51-2.49 (m, 1H), 2.43-2.34 (m, 3H) 1.17 (s, 9H)

BIOLOGICAL ASSAY

The present invention will be further described with reference to thefollowing test examples, but the examples should not be considered aslimiting the scope of the invention.

The experimental methods in the following examples for which no specificconditions are indicated will be carried out according to conventionalconditions or recommended conditions of the raw materials and theproduct manufacturer. The experimental reagents for which no specificsources are indicated will be conventional reagents generally purchasedfrom market.

Test Example 1: Biological Activity of the Compounds of the PresentInvention on

The Inhibition of Factor XIa Detected by Absorption Photometry

1. Experimental Materials

Enzyme: Coagulation Factor XIa protease (Abcam, Art. No ab62411)

Substrate: Coagulation Factor XIa specific substrate (HYPHEN1310 med,Art. No. Biophen cs-21(66))

Buffer: 100 mM tris-HCl, 200 mM NaCl, 0.02% Tween20, pH 7.4

2. Experimental Procedure

20 mM of test compound dissolved in 100% DMSO was diluted to 200, 20, 2,0.2, 0.02, 0.002 μM with 100% DMSO; 1 μl of the compound was added toeach well in a 384-well plate, blank and control wells were replacedwith DMSO. The plate was centrifuged to remove the compound to thebottom. 10 μl (2.5 μg/ml) of FXIa enzyme solution was added to eachwell, and 10 μl of buffer was added to the blank well. The plate wascentrifuged to remove the enzyme solution to the bottom.

Finally, 10 μl of 2 mM substrate were added to each well, and the platewas centrifuged to remove the substrate solution to the bottom.

The plate was incubated for 10 minutes at 37° C.; and then theabsorbance was measured at 405 nm. The absorbance was curve-fitted bygraphpad and the IC₅₀ obtained is shown in Table 1.

TABLE 1 IC₅₀ of the compounds of the present invention on the inhibitionof factor XIa Compound No. IC₅₀(FXIa)/(nM) 1 34 2 19 3 1741 4 39 5 16 61817 7 34 8 17 9 14 11 13 12 42 13 46 16 100 18 56 19 5690 20 36 21 3623 24 24 36 25 1523 26 21 27 66 29 90 37 29 38 30 39 38 40 38 41 39 4240 43 47 44 53 45 69 46 71 47 82 63 55 64 58 65 43 66 34 67 35 68 47 6949 70 54 71 46 72 21 74 100 75 100 76 100 78 72 79 45 80 40 81 2678 8268 83 >10000 84 42 85 92 86 99 87 73 88 74 89 42 90 100 91 50 92 21 9342 94 24 95 7513 96 32 97 36 98 40 99 29 100 35 101 23 102 8213 103 70104 8146 105 30 108 12 109 5456 110 53 111 18 112 >10000 113 33 114 27115 >10000 119 45 120 49 121 67 122 100 123 100 124 100 141 66 146 37147 56 155 81 158 46 159 33 160 68 161 13110 162 35 163 9114 164 30 16642 167 92 168 43 171 35 172 8918 173 100 176 71 177 27 178 7956 179 31180 4834

Conclusion: The compounds of the present invention have significantinhibition effects on FXIa.

Test Example 2: Determination of In Vitro Anticoagulant Effect of theCompounds of the Present Invention on Human Blood

1. Experimental Materials

Plasma: Human blood was collected in blood collection tubes containingno anticoagulant, and then 3.8% sodium citrate (volume ratio 1:9) wasadded. The tubes were centrifuged at 2500 rpm for 10 minutes at roomtemperature, and then the plasma was collected and stored at −80° C.;

Reagents: APTT reagent (Activated partial thromboplastin time assay kit,SIEMENS, Art. No. B4218-1), calcium chloride solution;

Instrument: Coagulation instrument (SYSMEX, CA-500).

2. Experimental Testing

The divided plasma was melted at room temperature and mixed well. 10000μM the test compound dissolved in 100% DMSO was diluted to 3000, 300,200, 150, 75, 30, 10, 3, 0.3 μM with 100% DMSO, and the blank was 100%DMSO. The reagent, plasma, and compound were placed in correspondingpositions in the coagulation instrument, and APTT detection of thecompound was carried out.

3. Data Analysis

Curve fitting was carried out by graphpad and CT2 was calculated, i.e.,the concentration of the compound corresponding to 2 times the APTT ofthe blank control. The results are shown in Table 2.

TABLE 2 CT2 of anticoagulant effect in vitro of the compounds of thepresent invention on human blood Compound No. Inhibition of plateletaggregation CT₂ (μM) 1 4.4 2 2.9 3 >10000 5 2.0 6 >10000 8 6.4 9 2.4 114.2 13 6.0 20 6.5 31 8.5 37 7.8 39 8.3 80 7.9 81 >10000 85 6.5 89 5.7 912.1 92 1.2 93 2.9 94 2.2 96 6.7 97 5.4 98 7.6 99 3.5 100 3.3 104 >10000105 6.9 108 1.4 109 >10000 111 3.2 112 >10000 114 3.6 160 3.8 163 >10000164 6.4 166 7.2 177 1.5 178 >10000 179 3.3 180 >10000 181 2.3 183 2.6184 >10000

TABLE 3 Comparison of CT2 of anticoagulant effect in vitro of thecompounds of the present invention with similar compounds in thepublished patents on human blood Compound No. Inhibition of plateletaggregation CT₂ (μM) 114 2.9 Comparative Example 2 13.1

Conclusion: It can be seen from Table 2 that the compounds of thepresent invention have significant anticoagulant effect on human blood.It can be seen from Table 3 that the CT2 value of Example 114 of thepresent invention is 4.5 times that of comparative Example 2 (Example186). The structural difference between the two compounds only lies inthat the substituents on position R¹ are different, fully indicatingthat R¹ in formula (AI) being —C(O)R⁷ has an unexpected effect on theanticoagulant effect of the entire molecular structure.

Pharmacokinetics Evaluation Test Example 3. Pharmacokinetics Assay ofthe Compounds of the Present Invention

1. Abstract

Rats were used as test animals. The drug concentration in plasma atdifferent time points was determined by LC/MS/MS after intragastricaladministration of the compounds of Example 5, Example 9, Example 11,Example 13, Example 29, Example 31, Example 80, Example 84, Example 108,Example 111, Example 114, Example 160, Example 171 and ComparativeExample 1 to the rats. The pharmacokinetic behavior of the compounds ofthe present invention was studied and evaluated in rats.

2. Test Protocol

2.1 Test Compounds

Compounds of Example 5, Example 9, Example 11, Example 13, Example 29,Example 31, Example 80, Example 84, Example 108, Example 111, Example114, Example 160, Example 171 and Comparative Example 1.

2.2 Test Animals

56 healthy adult Sprague-Dawley (SD) rats, half male and half female,were purchased from SINO-BRITSH SIPPR/BK LAB. ANIMAL LTD., CO, withLicense No.: SCXK (Shanghai) 2008-0016.

2.3 Preparation of the Test Compounds

A certain amount of the test compound was weighed, and added with 5% byvolume of DMSO, 5% by volume of Tween 80 and 90% normal saline toprepare a 0.2 mg/mL colorless, clear and transparent solution.

2.4 Administration

After an overnight fast, SD rats were intragastrically administered at adose of 2.0 mg/kg and an administration volume of 10.0 mL/kg.

3. Process

The rats were intragastrically administered the test compounds ofExample 5, Example 9, Example 11, Example 13, Example 29, Example 31,Example 80, Example 84, Example 108, Example 111, Example 114, Example160, Example 171 and Comparative Example 1. Blood (0.2 mL) was takenfrom the orbital sinus before administration and at 0.5, 1.0, 2.0, 4.0,6.0, 8.0, 11.0 and 24.0 hours after administration. The samples werestored in heparin anticoagulation tubes, and centrifuged for 10 minutesat 3500 rpm at 4° C. to separate the blood plasma. The plasma sampleswere stored at −20° C. The rats were fed 2 hours after administration.

The content of the test compound in the plasma of rats afterintragastric administration of different concentrations of the drug wasdetermined: 25 μL of rat plasma at each time after administration wastaken and added with 30 μL (100 ng/mL) of the internal standard solutionof camptothecin and 200 μL of acetonitrile, shaken vertically for 5minutes, and centrifuged for 10 minutes (4000 rpm). 3.0 μL of thesupernatant was taken from the plasma samples for LC/MS/MS analysis.

4. Results of Pharmacokinetic Parameters

Pharmacokinetic parameters of the compounds of the present invention inrats are shown below.

Pharmacokinetics Experiment 2 mg/kg Mean Apparent Plasma Area UnderResidence Distribution Concentration Curve Half-Life Time ClearanceVolume Example Cmax AUC T½ MRT CLz/F Vz/F No. (ng/mL) (ng/mL * h) (h)(h) (ml/min/kg) (ml/kg) 5 244 ± 77 518 ± 63  0.89 ± 0.08 6.64 ± 1.7765.1 ± 8.1  4981 ± 291  9 128 ± 50 701 ± 615 5.55 ± 1.79 6.78 ± 2.3669.8 ± 35.2 31483 ± 16061 11  73.1 ± 32.3 125 ± 50  1.53 ± 0.33 2.12 ±0.17   299 ± 110.9 40229 ± 18630 13   119 ± 78.0 241 ± 168 1.67 ± 0.482.36 ± 1.05 217 ± 151 26944 ± 14004 29 167 ± 45 382 ± 98  6.06 ± 2.995.00 ± 2.57 92.5 ± 28.3 45447 ± 16465 31 234 ± 66 414 ± 77  3.20 ± 1.413.24 ± 0.93 82.5 ± 14.6 21574 ± 6313  80   126 ± 50.0  158 ± 45.0 0.85 ±0.14 1.85 ± 0.76  222 ± 55.7 15822 ± 2288  108 105 ± 23 452 ± 44  6.98 ±1.22 7.33 ± 0.48 74.3 ± 6.9  44364 ± 3451  111 252 ± 56 378 ± 98  4.94 ±2.33 4.41 ± 1.99 94.1 ± 30.8 36730 ± 13669 114  91.2 ± 51.3 168 ± 1021.11 ± 0.25 1.67 ± 0.23 278 ± 182 24049 ± 11053 160  53.9 ± 20.3 365 ±52  4.34 ± 0.35 8.30 ± 1.33 92.5 ± 12.3 34577 ± 4126  171  462 ± 116 701± 175 1.45 ± 0.32 1.71 ± 0.32 49.9 ± 12.5 6236 ± 2146 84 48.8 ± 8.8 54.6± 19.1 0.68 ± 0.14 1.20 ± 0.20   673 ± 235.2 37947 ± 8230  Comparative 7.02 ± 2.97 7.27 ± 3.37 — — — — Example 1

Conclusion: The pharmacological absorption of the compounds of thepresent invention in rats is good, especially in the comparison ofExample 84 with Comparative Example 1 (Example 185), the Cmax diferenceof the two is 6.9 times, and the AUC difference is 7.5 times. Thestructural difference of the two is mainly at R¹ position, i.e., thecorresponding position in Example 84 is an acetyl group, and thecorresponding position in Comparative Example 1 is a cyano group, fullyindicating that R¹ in formula (AI) of the present invention being—C(O)R⁷ remarkably improves the pharmacological absorption of thecompound. Therefore, the compounds of the present invention havepharmacokinetic advantages.

Test Example 4: Determination of APTT Value and Pharmacokinetic Assay inCynomolgus Monkey

1. Test Purposes

Cynomolgus monkeys were used as test animals, and the APTT value atdifferent times after the oral administration of the compound of Example5 and the compound of Example 108 was measured by a coagulationinstrument, and the pharmacodynamic properties were evaluated.

Cynomolgus monkeys were used as test animals. The drug concentration inplasma at different time points was determined by LC/MS/MS afterintragastrical administration of the compounds of Example 5 and Example108 to the cynomolgus monkey. The pharmacokinetic behavior of thecompounds of the present invention was studied and evaluated in thecynomolgus monkeys.

2. Test Animals

Six male cynomolgus monkeys (101, 102, 103, 201, 202 and 203) werepurchased from Guangxi Xiongsen Primate Experimental Animal BreedingDevelopment Co., Ltd.

3. Test Compounds

Compounds of Example 5 and Example 108.

4. Preparation of the Test Compounds

A certain amount of the test compound was weighed, and added with 2% byvolume of DMSO, 78% by volume of PEG400 and 20% CMC-Na (0.5%) to preparea 3.0 mg/mL colorless, clear and transparent solution.

5. Administration

After an overnight fast, cynomolgus monkeys were intragastricallyadministered at a dose of 15.0 mg/kg and an administration volume of 5.0mL/kg.

6. Test Protocol for Determination of APTT Value in Cynomolgus Monkeys

6.1 Experimental Materials

Reagents: APTT reagent (Activated partial thromboplastin time assay kit,SIEMENS, Art. No. B4218-1), PEG-400 and CMC-Na;

Instrument: Coagulation instrument (SYSMEX, CA-500).

6.2 Collection and Processing of APTT Plasma Sample

Blood was taken before administration and at 1 hour, 2 hours, 4 hours, 8hours and 12 hours after administration. About 1.8 mL of blood was takenthrough femoral vein puncture in each animal for each time.Anticoagulated sodium citrate was added. After the blood sample wascollected, it was placed in a pre-labeled centrifuge tube, and theplasma was separated by centrifugation (centrifugation conditions: 3500rpm, 10 minutes, 2-8° C.). The plasma was stored in a −80° C.refrigerator for APTT assay.

6.3 APTT Assay Results in Cynomolgus Monkeys

TABLE 4 Determination results of APTT value of the compounds of thepresent invention in cynomolgus monkeys APTT (sec) Before No. AnimalAdministration 1 hour 2 hours 4 hours 8 hours 12 hours Example 5 10117.3 25.9 31.4 26.1 32.5 23.8 102 19.1 — 27.2 22.2 24.8 23.9 103 17.236.8 33.3 28.3 27.3 28.6 Example 201 17.5 26.3 27.5 28.7 26.9 27.3 108202 18.5 31.2 27.1 24.1 20.3 19 203 17.6 31.9 28.5 28.6 26.3 21.5

Conclusion: The compounds of the present invention has a significantprolongation of the APTT value in cynomolgus monkeys, indicating thatthe compounds of the present invention have a good anticoagulant effect.

7. Test Protocol of Pharmacokinetics Assay in Cynomolgus Monkeys

7.1 Experimental Process

The cynomolgus monkeys were intragastrically administered the compoundsof Example 5 and Example 9. 1.0 mL of blood was taken from the forelimbvein before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24hours after administration. The samples were stored in heparinanticoagulation tubes, and centrifuged for 10 minutes at 3500 rpm toseparate the blood plasma. The plasma samples were stored at −80° C. Therats were fed 2 hours after administration.

The content of the test compound in the plasma of cynomolgus monkeysafter intragastric administration of different concentrations of thedrug was determined: 25 μL of cynomolgus monkey plasma at each timeafter administration was taken and added with 30 μL (100 ng/mL) of theinternal standard solution of camptothecin and 225 μL of acetonitrile,shaken vertically for 5 minutes, and centrifuged for 10 minutes (4000rpm). 1.0 μL of the supernatant was taken from the plasma samples forLC/MS/MS analysis.

7.2. Results of Pharmacokinetic Parameters in Cynomolgus Monkeys

Pharmacokinetic parameters of the compounds of the present invention incynomolgus monkeys are shown below.

Pharmacokinetics Experiment 15 mg/kg Mean Apparent Plasma Area UnderResidence Distribution Concentration Curve Half-Life Time ClearanceVolume Cmax AUC T½ MRT CLz/F Vz/F No. (ng/mL) (ng/mL * h) (h) (h)(ml/min/kg) (ml/kg) Example 5 688 ± 560 4953 ± 2881 5.86 ± 1.10 9.63 ±0.78 62 ± 32 30409 ± 12559 Example 108 295 ± 102 2701 ± 1344 6.32 ± 1.478.81 ± 3.65 120 ± 83  59145 ± 26224

Conclusion: The compounds of the present invention have goodpharmacological absorption in cynomolgus monkeys and havepharmacokinetic advantages.

What is claimed is:
 1. A compound of formula (AI):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, wherein: ring A is an aryl or a heteroaryl; R¹ is—C(O)R⁷; each R² is identical or different, and each is independentlyselected from the group consisting of hydrogen, halogen, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy,hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R³ isselected from the group consisting of halogen, alkyl, haloalkyl, alkoxy,cycloalkyloxy, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyland alkylthio, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy,hydroxyalkyl and alkylthio are each optionally substituted by one ormore groups selected from the group consisting of deuterium, halogen,alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy and hydroxyalkyl; R⁴ isselected from the group consisting of hydrogen, alkyl, alkoxy,haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryland heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl are each optionally substituted by one or more R⁹ groups;each R⁵ is identical or different, and each is independently selectedfrom the group consisting of hydrogen, alkyl, alkoxy, oxo, halogen,haloalkyl, haloalkoxy, amino, nitro, cyano, hydroxy, hydroxyalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R⁸, —C(O)OR⁸,—NHC(O)R⁸, —NHC(O)OR⁸, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —CH₂NHC(O)OR⁸,—CH₂NR¹⁰R¹¹, —C(O)OCH(R¹⁰)R¹¹ and —S(O)_(m)R⁸, wherein the alkyl isoptionally substituted by one or more groups selected from the groupconsisting of deuterium, halogen, alkoxy, haloalkoxy, amino, nitro,cyano, hydroxy, hydroxyalkyl, —NR¹⁰R¹¹ and —NHC(O)OR⁸; R⁷ is selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryland heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,aryl and heteroaryl are each optionally substituted by one or moregroups selected from the group consisting of hydrogen, deuterium,halogen, alkyl, alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy,hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl andheteroaryl; R⁸ is selected from the group consisting of hydrogen, alkyl,haloalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl andheteroaryl; R⁹ is selected from the group consisting of hydrogen,deuterium, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano,hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl andheteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroarylare each optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino,nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy,heterocyclyl, —NHC(O)R¹² and R¹³; R¹⁰ and R¹¹ are identical ordifferent, and each is independently selected from the group consistingof hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, —C(O)OR⁸ and—OC(O)OR¹², wherein the cycloalkyl and heterocyclyl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl, alkoxy, haloalkyl, oxo, amino, nitro, cyano,hydroxy and hydroxyalkyl; R¹² is selected from the group consisting ofhydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, cycloalkyl,heterocyclyl, aryl and heteroaryl; R¹³ is aryl or heteroaryl, whereinthe aryl and heteroaryl are each optionally substituted by one or moregroups selected from the group consisting of hydrogen, deuterium,halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy,hydroxyalkyl, cycloalkyl, cycloalkyloxy and heterocyclyl; n is 0, 1, 2,3 or 4; m is 0, 1 or 2; and s is 0, 1, 2, 3 or
 4. 2. The compoundaccording to claim 1, being a compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, ormixture thereof, or a pharmaceutically acceptable salt thereof, wherein:L¹ is alkylene, wherein the alkylene is optionally substituted by one ormore halogens or deuteriums; R⁶ is selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, alkoxy, amino, nitro, cyano,hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl andheteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroarylare each optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino,nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy,heterocyclyl, —NHC(O)R¹² and R¹³; R¹² is selected from the groupconsisting of hydrogen, alkyl, haloalkyl, amino, cycloalkyl,heterocyclyl, aryl and heteroaryl; R¹³ is aryl or heteroaryl, whereinthe aryl and heteroaryl are each optionally substituted by one or moregroups selected from the group consisting of hydrogen, deuterium,halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy,hydroxyalkyl, cycloalkyl, cycloalkyloxy and heterocyclyl; and ring A,R¹˜R³, R⁵, n and s are as defined in claim
 1. 3. The compound ofaccording to claim 2, being a compound of formula (Iaa):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof ormixture thereof, or a pharmaceutically acceptable salt thereof, wherein:ring A, L¹, R¹˜R³, R⁵˜R⁶, n and s are as defined in claim
 2. 4. Thecompound according to claim 1, wherein

is selected from the group consisting of:

wherein R⁵ and s are as defined in claim
 1. 5. The compound according toclaim 2, being a compound of formula (II):

or a tautomer, mesomer racemate enantiomer, diastereomer thereof ormixture thereof, or a pharmaceutically acceptable salt thereof, wherein:R⁷ is selected from the group consisting of alkyl, cycloalkyl andhaloalkyl, wherein the alkyl and cycloalkyl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl and cycloalkyl; and L¹, R², R³, R⁵, R⁶ and nare as defined in claim
 2. 6. The compound according to claim 1, whereineach R⁵ is identical or different, and each is independently selectedfrom the group consisting of alkyl, alkoxy, oxo, halogen, haloalkyl,cyano, hydroxy, —C(O)OR⁸, —NHC(O)OR⁸, —C(O)NR¹⁰R¹¹, —CH₂NHC(O)OR₉,—CH₂NR¹⁰R¹¹, —C(O)OCH(R¹⁰)R¹¹ and —S(O)_(m)R⁸; R⁸ is selected from thegroup consisting of hydrogen, alkyl, hydroxy and amino; R¹⁰ and R¹¹ areidentical or different, and each is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, cycloalkyl,heterocyclyl, —C(O)OR⁸ and —OC(O)OR¹², wherein the cycloalkyl andheterocyclyl are each optionally substituted by one or more groupsselected from the group consisting of deuterium, halogen, alkyl, alkoxy,haloalkyl, oxo, amino, nitro, cyano, hydroxy and hydroxyalkyl; and R¹²is alkyl.
 7. The compound of formula (AI) according to claim 1, whereinR¹ is —C(O)R⁷; R⁷ is selected from the group consisting of alkyl,cycloalkyl and haloalkyl, wherein the alkyl and cycloalkyl are eachoptionally substituted by one or more groups selected from the groupconsisting of deuterium, halogen, alkyl and cycloalkyl.
 8. The compoundaccording to claim 2, being a compound of formula (III):

or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof ormixture thereof, or a pharmaceutically acceptable salt thereof, wherein:each R⁵ is identical or different, and each is independently selectedfrom the group consisting of alkyl, alkoxy, oxo, halogen, haloalkyl,cyano, hydroxy, —C(O)OR⁸, —NHC(O)OR⁸, —C(O)NR¹⁰R¹¹, CH₂NHC(O)OR⁸,—CH₂NR¹⁰R¹¹, —C(O)OCH(R¹⁰)R¹¹ and —S(O)_(m)R⁸; R⁸ is selected from thegroup consisting of hydrogen, alkyl, hydroxy and amino; R¹⁰ and R¹¹ areidentical or different, and each is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, cycloalkyl,heterocyclyl, —C(O)OR⁸ and —OC(O)OR¹², wherein the cycloalkyl andheterocyclyl are each optionally substituted by one or more groupsselected from the group consisting of deuterium, halogen, alkyl, alkoxy,haloalkyl, oxo, amino, nitro, cyano, hydroxy and hydroxyalkyl; R¹² isalkyl; R⁷ is selected from the group consisting of alkyl, cycloalkyl andhaloalkyl, wherein the alkyl and cycloalkyl are each optionallysubstituted by one or more groups selected from the group consisting ofdeuterium, halogen, alkyl and cycloalkyl; and L¹, R², R³, R⁶ and n areas defined in claim
 2. 9. The compound according to claim 8, being acompound of formula (IV):

wherein: L¹, R², R³, R⁶, R⁷ and n are as defined in claim
 8. 10. Thecompound according to claim 1, wherein R² is halogen; and n is 0, 1 or2.
 11. The compound according to claim 1, wherein R³ is alkoxy, whereinthe alkoxy is optionally substituted by one or more deuteriums orhalogens.
 12. The compound according to claim 2, wherein L¹ is —(CR¹⁴₂)_(x)—, x is an integer of 1, 2, 3, 4; or 4; R¹⁴ is hydrogen ordeuterium; R⁶ is selected from the group consisting of hydrogen,deuterium, halogen, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl,aryl and heteroaryl are each optionally substituted by one or moregroups selected from the group consisting of deuterium, halogen, alkyl,alkoxy, cycloalkyl, heterocyclyl, —NHC(O)R¹² and R¹³; R¹² is alkyl orcycloalkyl; R¹³ is aryl or heteroaryl, wherein the aryl and heteroarylare each optionally substituted by one or more groups selected from thegroup consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, amino,nitro, cyano and hydroxy.
 13. The compound according to claim 2, whereinL¹ is —CH₂— or —CD₂-; R⁶ is selected from the group consisting ofcycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl,heterocyclyl, aryl and heteroaryl are each optionally substituted by oneor more groups selected from the group consisting of deuterium, halogen,alkyl, alkoxy, cycloalkyl, heterocyclyl, —NHC(O)R¹² and R¹³; R¹² isalkyl or cycloalkyl; R¹³ is aryl or heteroaryl, wherein the aryl andheteroaryl are each optionally substituted by one or more groupsselected from the group consisting of deuterium, halogen, alkyl, alkoxy,haloalkyl, amino, nitro, cyano and hydroxy.
 14. The compound accordingto claim 2, wherein L¹ is —CH₂CH₂—; and R⁶ is alkyl, alkoxy orcycloalkyloxy.
 15. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 16. A process forpreparing the compound of formula (AI) according to claim 1, comprising:

condensing a compound of formula (AI-A) with a compound of formula(AI-B) or a hydrochloride thereof under an alkaline condition to obtaina condensation product, optionally hydrolyzing the condensation productunder an alkaline condition to obtain compound of formula (AI); wherein:ring A, R¹˜R⁵, n and s are as defined in claim
 1. 17. A process forpreparing the compound of formula (I) according to claim 2, comprising:

condensing a compound of formula (I-A) with a compound of formula (AI-B)or a hydrochloride thereof under an alkaline condition to obtain acondensation product, optionally hydrolyzing the condensation productunder an alkaline condition to obtain the compound of formula (I);wherein: ring A, L¹, R¹˜R³, R⁵˜R⁶, n and s are as defined in claim 2.18. A pharmaceutical composition comprising the compound according toclaim 1, and one or more pharmaceutically acceptable carriers, diluentsor excipients.
 19. A method for preventing and/or treating a factor XIamediated disease, comprising administering to a patient in need thereofan effective amount of the pharmaceutical composition according to claim18.
 20. A method for preventing and/or treating a cardiovascular andcerebrovascular disease, comprising administering to a patient in needthereof an effective amount of the pharmaceutical composition accordingto claim
 18. 21. A method for inhibiting factor XIa, comprisingadministering to a patient in need thereof an effective amount of thepharmaceutical composition according to claim 18.